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International audience; Paediatric sarcoidosis is an extremely rare disease characterized by a granulomatous inflammation. The estimated incidence is 0.6–1.02/100,000 children, but in the absence of international registers, the disease is probably under-reported. Its pathophysiologic basis is not clearly understood but the current hypothesis is a combination of a genetic predisposition and an environmental exposure that could be either organic or mineral. Contrary to adult forms of the disease, general symptoms are often at the forefront at diagnosis. In its most frequent form, paediatric sarcoidosis is a multi-organ disorder affecting preferentially the lungs, the lymphatic system and the liver, but all organs can be affected. This review aims to provide an overview of current knowledge on sarcoidosis in children, providing a summary of the data available from cohort studies on the presentation, the management and the evolution of the disease in this specific population.

Introduction La sarcoidose est une granulomatose systemique d’etiologie indeterminee [1] . De nombreux cas et des series d’infections opportunistes (IO) chez des patients atteints de sarcoidose sont rapportes dans la litterature medicale [2] , [3] . Sont generalement exclues les aspergilloses cavitaires et les tuberculoses, associees respectivement a la fibrose et a des elements demographiques communs. Les agents opportunistes rapportes sont varies (Cryptococcus neoformans, JC virus, mycobacteries atypiques, Nocardia spp.) mais actuellement aucun facteur de risque d’infection opportuniste n’est decrit au cours de la sarcoidose. Patients et methodes Nous avons effectue un recueil de la litterature medicale via le moteur de recherche Medline et realise un appel a observations via le groupe sarcoidose francophone a la recherche d’associations « infection opportuniste » et « sarcoidose ». Les caracteristiques cliniques des IO ont ete comparees a une population temoin constituee de patients porteurs d’une sarcoidose sans IO issus d’une cohorte de notre service. Resultats La revue de la litterature a permis de recenser 164 cas d’infections qualifiees d’opportunistes chez des patients porteurs d’une sarcoidose. Parmi ces 164 infections, 83 etaient des cryptococcoses (51 %) et 39 etaient des leuco-encephalopathies multifocales progressives (LEMP) (24 %). Notre appel a observations a permis de recenser 50 IO chez 49 patients, incluant : 24 cryptococcoses (49 %), 12 LEMP (24 %), 7 pneumocystoses (14 %) et 7 autres infections (14 %) dont 3 mycobacterioses atypiques, 2 nocardioses et 2 infections a cytomegalovirus. Ces 49 patients avec IO ont ete compares a 135 controles porteurs d’une sarcoidose sans IO. Dans le groupe infection opportuniste, le compte lymphocytaire moyen etait de 1000/mm3 (100-2680/mm3) et 14 patients ne presentaient pas de lymphopenie (29 %). Les facteurs de risques identifies en analyse univariee etaient : le sexe masculin (OR = 4,76; IC95 % [2,12 ; 10,00]), la presence d’adenopathies peripheriques (OR = 3,45 ; [1,49 ; 8,04]), d’une hepatomegalie (OR = 8,10 ; [1,91 ; 40,41]) ou d’une splenomegalie (OR = 9,00, [1,80 ; 58,86]), la presence d’une atteinte pulmonaire de stade ≥2 (OR = 6,66 ; [2,80 ; 17,74]), d’une atteinte neurologique centrale (OR = 8,73 ; [1,98 ; 53,52]) ou d’une insuffisance renale (OR = 5,65 ; [1,33 ; 25,24]), la corticotherapie (OR = 10,26 ; [4,15 ; 29,22]) et l’utilisation du cyclophosphamide (OR = 9,42 ; [1,61 ; 98,92]) ou d’un anti-TNFα (OR = 7,68 ; [1,21 ; 83,62]). En analyse multivariee (ajustement sur l’âge et le sexe), les facteurs de risque identifies etaient l’utilisation de corticoides (OR = 10,60 ; [4,31 ; 29,57]) ou d’un anti-TNFα (OR = 13,47 ; [2,05 ; 129,43]), la presence d’une hepatomegalie (OR = 9,91 ; [2,23 ; 55,85]), une atteinte pulmonaire de stade 2 ou superieur (OR = 5,65 ; [2,34 ; 15,36]) et l’insuffisance renale (OR = 11,76 ; [2,32 ; 68,35]). La lymphopenie Conclusion Les facteurs de risque d’IO dans notre etude sont associes a la gravite de la sarcoidose et/ou a sa diffusion systemique. Il existe un facteur confondant lie a l’utilisation des immunosuppresseurs chez des patients avec une sarcoidose plus severe. Dans notre serie, 6 % des patients ont developpe une infection opportuniste sans aucun facteur de risque, suggerant neanmoins une immunosuppression propre a la sarcoidose dans ces cas.

Summary Lynch syndrome is due to germline mutations in mismatch repair genes: MLH1, MSH2, MSH6 and PMS2. It is characterized by an increased risk of various cancers including colorectal and endometrial cancers. Early diagnosis of these patients allows for appropriate surveillance and improves survival rates. Differentiating between patients who should undergo genetic testing and those for whom it is not necessary is difficult despite various established criteria (Amsterdam and Bethesda). Often, health professionals meet in multidisciplinary committees (MDC) to discuss patient cases regarding Lynch syndrome. In this study, we evaluated if the prediction model PREMM 1,2,6 could be used to enhance MDC decision-making and whether it should be included in our own routine practice and in those of other French teams. Using the prediction model in our cohort would have avoided 12% of the analyses recommended by our MDC. Furthermore, all patients with a mutation in one of the MMR genes would have been detected. In addition, according to the model, we should have provided 20% more genetic testing, which suggests that the decision-making criteria used by the professionals in our MDC, was too restrictive. These results suggest that PREMM 1,2,6 should be used in current practice to validate the decisions of the MDC before genetic testing is performed in complex cases. The model should be added as a major quality criterion for genetic testing, along with somatic tests, as previously reported in the literature.

Introduction La sarcoidose est une maladie granulomateuse qui affecte principalement les poumons et dont le determinisme multifactoriel associe des facteurs environnementaux et genetiques. Nous avons publie en 2018 une analyse complete d’exome de cas pediatriques suggerant des anomalies dans l’autophagie, le cycle cellulaire et les processus de reponse immunitaire innee. Notre etude actuelle se focalise sur les formes familiales a presentation autosomique dominante et penetrance forte, afin de mettre en evidence des mutations deleteres agissant comme des triggers puissants de la predisposition. Methodes Nous avons sequence un total de 22 sujets, dont 14 malades et 8 controles internes sains, appartenant a 5 familles predisposees a la sarcoidose. Le protocole de sequencage est base sur la methodologie d’enrichissement en solution Agilent (SureSelect, Agilent) (Human Clinical Research Exome, Agilent), suivie d’un sequencage massif parallele sur Illumina HiSEQ 4000. La selection des variants geniques est basee sur la faible frequence allelique (MAF Resultats La selection des genes a permis d’identifier une serie de 192 genes dont 52 (27 %) semblent etre concentres autour de centres fonctionnels de Rac1 Rho GTPase et le hub du complexe mTor ( Fig. 1 ). Ces resultats ont ete confirmes par des methodes d’enrichissement de reseaux fonctionnels tel ConsensusPathDB. Un nombre significatif de mutations deleteres a egalement ete observe dans des genes codant pour des facteurs intrinseques de l’autophagie et du transport vesiculaire. Une analyse retrospective de 196 patients versus temoins suggere une concentration de mutations dans les genes regulateurs de Rac1 dans 4 % des cas, chez des patients presentant des formes severes, chroniques, multisystemiques et/ou evolutives de la maladie. Conclusion Notre travail suggere que la predisposition genetique a la sarcoidose pourrait etre liee a un effet combine de mutations deleteres de genes impliques dans la regulation de l’autophagie et des hubs fonctionnels Rac1 et mTor, ouvrant la voie a un depistage precoce des formes les plus evolutives.

CD4+ T lymphocytes play a major role in the pathophysiology of sarcoidosis. Many studies have investigated the immunological and genetic abnormalities in this disease. There are few studies concerning the metabolic pathways. Essentially they concern the pathways: STAT1, MAPK38, NF-κB, Galphai, cAMP and cGMP PDE and PEMT1. Using studies in the literature and results of our own work concerning some metabolic aspects of T lymphocytes in sarcoidosis, we present a revue of the various hypotheses, which involve dysfunction of cAMP signaling pathways, such as RAS/RAF/MEK/ERK in T lymphocytes, leading to a disorder of immunity.

Introduction La sarcoidose reste une maladie d’etiologie meconnue. Les approches explicatives sont actuellement environnementales et/ou genetiques. Les hypotheses fonctionnelles et biochimiques ont aborde les voies de signalisation : NFkB, STAT1, Galphai, RIP2, IRAK et plus recemment mTOR. L’etude nationale SARCFAM [1] a permis de collecter plus de 150 familles presentant une predisposition a la maladie. Methodes Au sein de cette cohorte, six familles reunissant au moins deux ou trois sujets malades et un ou deux temoins sains ont pu beneficier d’une etude en WES. Le sequencage a ete realise sur Illumina HiSEQ2500 en cooperation avec INTEGRAGEN et les donnees sources ont ete analysees par un pipeline informatique developpe au sein de l’equipe suivant les recommandations du Broad Institute ( https://www.broadinstitute.org/gatk/guide/best-practices ). Tous les cas et temoins ont ete sequences deux fois dans des protocoles independants et seuls les resultats reproductibles ont ete retenus. Une selection de variants geniques a ete confirmee par sequencage SANGER. Resultats Les resultats montrent : (a) que cette maladie presente une tres forte heterogeneite genetique, (b) que des variations genotypiques entre patients d’une meme famille sont susceptibles d’expliquer une expressivite variable de la maladie, (c) qu’il existe une forte concentration de mutations dans la sphere immunologique, (d) que ces mutations interessent les voies de signalisation et de regulation de l’autophagie autour des voies Rac1 et mTOR, (e) qu’il existe une concentration par famille de variants pathogenes in silico dans ces voies fonctionnelles, 3 a 8 pour Rac1, 2 a 6 pour mTOR et l’autophagie, suggerant une complementation des effets pathogenes a l’origine de la predisposition. Conclusion Ces observations conduisent a des hypotheses seduisantes sur un dysfonctionnement du processus d’autophagie rendant les malades plus vulnerables a divers facteurs de l’environnement. Elles permettent d’envisager des etudes fonctionnelles et des analyses genetiques sur une grande cohorte.

The Birt-Hogg-Dube (BHD) syndrome is associated with cutaneous disorders including fibrofolliculomas and trichodiscomas, and also lung pneumatocysts and kidney tumours. The BHD syndrome occurs as a consequence of an autosomal dominantly inherited genodermatosis, linked to multiple germline mutations in the 14 exons of the BHD gene, mapped on 17p11.2 and encoding for folliculin (FLCN). The size and number of lung pneumatocysts are extremely variable and the cysts are surrounded by normal pulmonary tissue. In the absence of smoking lung function is usually unimpaired. The lung cysts are frequently complicated by the development of recurrent pneumothoraces. Treatment of pneumothorax in patients with the BHD syndrome is similar to the approach taken for patients with spontaneous pneumothorax. Lung cysts in the BHD syndrome are a rare cause of cystic pulmonary lesions. However, they must be systematically evaluated since kidney tumours occur in one third of patients. We report a case of classical BHD syndrome with specific cutaneous involvement, recurrent pneumothoraces complicating lung cysts, an exon 12 germline mutation on BHD gene and a familial history suggesting other related cases. This observation allows us to update this orphan disease, to consider BHD in the differential diagnosis of lung cysts and, above all, to highlight the high frequency and the prognostic significance of associated kidney tumours.

Resume Objectif Detecter les anomalies chromosomiques majeures du melanome uveal enuclee, les correler a la survenue de metastases hepatiques et au deces. Patients et methodes Dix melanomes uveaux enuclees entre 2005 et 2008 a l’hopital de la Croix-Rousse de Lyon ont ete analyses retrospectivement par hybridation comparative genomique sur puce pangenomique 19 000 clones. Resultats Les desequilibres les plus frequents etaient une perte du chromosome 3 (8/10), un gain du 8q (7/10) ou du 8 entier (2/10) et un gain du 6p (2/10). La plupart des metastases (6/7) et tous les cas de deces (5/5) concernaient les tumeurs ayant la monosomie du chromosome 3 associee a un gain de 8q. Discussion et conclusion L’hybridation genomique comparative sur puce est une technique d’analyse pangenomique adaptee a l’etude du melanome uveal. La monosomie du chromosome 3, associee aux gains de 8q, sont frequents et fortement correles au mauvais pronostic de la tumeur. Les gains de 6q sont rares et de meilleur pronostic. Les desequilibres chromosomiques portant sur les chromosomes 3 et 6 sont mutuellement exclusifs dans notre serie. Ces donnees vont dans le sens de celles decrites dans la litterature.

Multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2) are major genetic disorders carrying a high risk of endocrine tumor development. The mutated genes were identified in 1993 (MEN2-RET) and 1997 (MEN1), enabling genetic testing and functional studies. Genetic analysis has led to new clinical and therapeutic strategies for MEN1/2 patients, and has improved our understanding of the pathways underlying the development of such tumors, which occur in an autosomal dominant manner and with high penetrance. The MEN1 gene encodes menin, a protein involved in many cell functions, such as transcription, genome stability, cell cycling and apoptosis. The MEN1 gene has 10 exons, and its exhaustive analysis in MEN1 patients helps guide their management. MEN2 is related to activating missense mutations in the RET protooncogene, which encodes a tyrosine kinase receptor (TKR). RET activation occurs upon autodimerization induced by the binding of specific ligands belonging to glial cell-derived neurotrophic factor-like family (GFL) proteins, regulated by coreceptors. The position of missense mutations--in the extracellular or intracellular TK domains--influences the aggressiveness of the most frequent malignancy, medullary thyroid carcinoma, establishing a genotype-phenotype correlation. We also briefly describe the genetic basis of three other inherited states predisposing individuals to endocrine tumors, namely Carney's syndrome, hyperparathyroidism type 2 (HRPT2) and familial isolated pituitary adenoma (FIPA), which are related to inactivating mutations in the PRKAR1-alpha, HRPT2 and AIP genes, respectively.

Mutations in LGI1 have been reported in several families with autosomal dominant lateral temporal epilepsy. In a family in which three patients also experienced migraine-like episodes we found a novel three base-pair deletion (c.377_379delACA), resulting in the deletion of an asparagine residue in the second leucine-rich repeat. Functional studies showed that the mutated protein was not secreted when transfected in COS cells, consistent with a causative role in the disease.

Wermer's syndrome or Multiple Endocrine Neoplasia Type-1 (MEN1) is an autosomal dominant inherited disease, related to mutations in MEN1, an approximately 10-kb gene encoding menin, localized on chromosome 11q13. The Endocrine Tumor Group (GTE) has set up a MEN1 observatory of 1001 regularly followed MEN1 cases. This observatory aims at registering and evaluating MEN1 cases in a large cohort. Any new study on a particular unexplored aspect of the disease may be proposed by a physician to the GTE. This article describes the way to diagnose a new MEN1 case and to register it. Procedures for participating in a new study are presented. Some original results are quoted.

Summary Few studies have concerned the rare functioning endocrine pancreatic tumors associated with multiple endocrine neoplasia type 1 (MEN 1). When sporadic, these tumors have a poor prognosis. Aim To analyze the frequency, characteristics and prognosis of MEN 1-associated glucagonomas, VIPomas and somatostatinomas recorded in the GTE ( Groupe des Tumeurs Endocrines ) registry. Methods Records of the patients whose GTE registry codes included glucagonoma, VIPoma or somatostatinoma were reviewed. The diagnosis was confirmed when there were clinical signs of a functioning tumor and/or when blood levels of the peptide were higher than twice the upper limit of normal. Results Among 580 patients with MEN 1, duodeno-pancreatic involvement was present in 307 (52.9%). Five (1.6%) had a glucagonoma, 3 (0.98%) a VIPoma and 2 (0.65%) a somatostatinoma. A clinical syndrome was present in 1 patient with glucagonoma, in the 3 with VIPomas and in 1 with somatostatinoma. Tumor size was greater than 3 cm more often for these rare tumours (67%) than in patients with other type of duodeno-pancreatic involvement (28%) (P = 0.02) and visceral metastases were more frequent (40% vs 15%; P = 0.056). Ten-year survival of patients with glucagonomas, VIPomas or somatostatinomas (53.8%; CI95%: 15.5-92.1) was poorer than that of patients with insulinomas (91.4%; CI95%: 83.399.5; P = 0.01) or gastrinomas (81.7%; CI95%: 74.9-88.5; P = 0.20) and close to that of patients with non-functioning tumors (62.2%, CI95%: 41.0-83.9; NS). Conclusion Glucagonomas, VIPomas and somatostatinomas, especially the functioning type, are very rare in patients with MEN 1. Prognosis is poor, probably because of large tumor size and high rate of metastasis. Survival is similar to that in patients with non-functioning tumors.

Menin, the product of the tumor suppressor gene MEN1, is widely expressed in mammalian endocrine and non-endocrine tissues, including intestine. Its known abundant expression in several types of cells with high proliferative capacity led us to investigate the physiological function of the protein menin in intestinal epithelium, one of the most rapidly growing epithelia. Here we showed that the Men1 gene is mainly expressed in the crypt compartment of the proximal small intestine and that its expression was increased during fasting in vivo, both suggesting a role of menin in the control of cell growth. Indeed, specific reduction of menin expression by transfected antisense cDNA in the rat duodenal crypt-like cell line, IEC-17, increased cell proliferation. The latter is correlated to a loss of cell-cycle arrest in G(1) phase by resting cells and an overexpression of cyclin D1 and cyclin-dependent kinase (Cdk)-4. Furthermore, these cells lost the inhibition of proliferation induced by transforming growth factor-beta1, associated with a decrease of transforming growth factor-beta type II receptor expression. As a result of deregulated proliferation, antisense menin transfected IEC-17 cells became tumorigenic as shown in vitro as well as in vivo in immunosuppressed animals. These results indicate that menin contributes to proliferation control in intestinal epithelial cells. The present study reveals an unknown physiological function for menin in intestine that may be important in the regulation of epithelial homeostasis.

Resume Parmi 408 cas de patients atteints de neoplasie endocrinienne multiple de type 1, 127 cas de gastrinomes ont ete individualises au sein de la cohorte du groupe de tumeurs endocrines (GTE) a la date de juillet 2000 (31,1 %). Le but de cette etude a ete d'evaluer les donnees cliniques, biologiques, chirurgicales, ainsi que leurs tendances sur trois periodes ( 1990). Un syndrome de Zollinger-Ellison (SZE) etait present dans 96 % des cas. L'âge moyen des premiers signes etait de 39,4 ans. Il existait 55,9 % d'hommes, 7,1 % des SZE etaient porteurs de metastases hepatiques synchrones. Les principaux elements evolutifs significatifs ont ete les suivants : diminution de la positivite des quatre tests biologiques diagnostiques pris isolement, meilleure reconnaissance de l'œsophagite (4,5 a 29,7 %), augmentation de la taille des tumeurs resequees (9,9 a 16,8 mm), reconnaissance d'un contexte familial (73,1 a 80 %), utilisation croissante de l'Octreoscan et de l'echoendoscopie contributives dans 81,3 et 92,3 % dans la detection des metastases et des tumeurs pancreatiques apres 1991, diminution des patients operes (96 a 52,5 %), diminution des patients operes du gastrinome (87,5 a 37,5 %), du tractus gastro-intestinal (70,8 a 30 %), augmentation relative des resections pancreatiques majeures enlevant le duodenum et la tete du pancreas (10 a 26,7 %), disparition de la mortalite operatoire. Six des sept patients (85,7 %) ayant eu une resection pancreatique majeure ont normalise la gastrinemie postoperatoire vs 15 % pour les autres techniques. La probabilite de survie etait de 90 ± 4,4 % a cinq ans, legerement amelioree apres 1985 (85 ± 4,8 % vs 95 ± 3,6, p = 0,1). Conclusion. – Les SZE des NEM1 ont ete pris en charge a un stade plus precoce et moins souvent operes. Cependant, l'incidence des metastases hepatiques synchrones n'a pas evolue significativement. Les indications operatoires se sont centrees sur l'urgence et la resection des masses tumorales pour prevenir les metastases et ce sans aucune mortalite apres 1991.

Resume La neoplasie endocrinienne multiple de type 1 est une maladie rare mais trompeuse. Son diagnostic doit etre evoque devant au moins deux atteintes cardinales de la maladie (hyperaparathyroidisme, atteinte pancreatique endocrinienne, atteinte hypophysaire) mais aussi devant un arbre genealogique avec des lesions repetees au fil des generations. Les atteintes non cardinales doivent etre recherchees pour orienter le diagnostic (surrenales, tumeur neuro-endocrine thymique et bronchique, atteinte cutanee, lipome, tumeur du systeme nerveux central). Toute prise en charge chirurgicale d’une atteinte sans savoir qu’elle s’integre a une NEM1 est vouee a l’echec. Les traitements specifiques par atteinte sont revus. Le diagnostic genetique est possible mais l’alteration n’est pas retrouvee dans tous les cas. En revanche, dans une famille ou la mutation est connue, un test genetique negatif permet un diagnostic d’exclusion. Le pronostic tient aux metastases hepatiques des gastrinomes et aux tumeurs thymiques rares (2,1 %) mais tres agressives. Il est de regle que toute atteinte endocrinienne chirurgicale apparemment isolee en particulier parathyroidienne doit faire chercher une atteinte des autres glandes endocrines et doit conduire a la constitution d’un arbre genealogique recherchant une atteinte mono glandulaire ou pluriglandulaire familiale.

Insulinomas associated with multiple endocrine neoplasia type 1. Report of a series of 44 cases by «the groupe d'etudes des neoplasies endocriniennes multiples type 1» (GENEM). Study aim: The aim of this retrospective study conducted by the « Groupe d'etude des neoplasies endocriniennes multiples type 1 » (GENEM) was to report a series of insulinomas associated with multiple endocrine neoplasias type 1 (NEM 1) and to determine the most appropriate strategy for the topographical exploration and surgical management. Patients and methods: From 1960 to 1996, 44 patients were included, 16 men and 28 women (mean age: 36,4 ± 13,9 years). This study concerned morphological investigations, tumoral features, modalities and results of the treatment. Results: Insulinomas were associated with other functional islet tumors in 15 patients: ZE syndrome (n = 8), glucagonoma (n = 6), vipoma (n = 1). Malignant lesions were present in 6 patients: isolated insulinomas (n = 2), insulinomas associated with ZE syndrome (n = 2) and vipoma (n = 1). The sensivity of the preoperative imaging procedures was less than 70 %. Fourty-one patients were operated on: subtotal pancreatectomy (n = 26 including cephalic enucleations in 8), enucleations (n = 8), total pancreatectomy (n = 3), pancreaticoduodenectomy with caudal enucleations (n = 1), and for 3 patients, no details were available. There was no postoperative mortality. Hyperinsulinism disappeared in 27 patients (including 2 after reoperation) with a mean follow-up of 9 years. Among 6 patients with malignant lesions, 3 were alive with a 3, 4 and 10 year-follow-up. Conclusion: Subtotal pancreatectomy with splenic conservation and enucleation of cephalic lesions is suggested as the procedure of choice in this group of patients. This procedure allows simplification of preoperative imaging investigations because lesions of the pancreatic head have only to be detected. Preoperative endoscopic ultrasonography and intraoperative ultrasonography are the best investigations.

The possible role of interleukin 10 (IL-10) as an endogenous inhibitor of CD23-driven inducible nitric oxide synthase (iNOS) expression in human macrophages was investigated. Cross-linking of CD23 by a monoclonal antibody induced iNOS mRNA, as detected by RT-PCR, and the production of NO measured as the stable derivative, nitrite. A linear correlation was observed between CD23 expression and iNOS activity or NO2- production. The iNOS activity reached a maximum 48 h after ligation of CD23, then declined rapidly until 72 h. In parallel, nitrite production was detected after 24 h and reached a maximum after 48 h. In addition, ligation of the CD23 molecule induced, in a time-dependent manner, the production of IL-10. As this cytokine is known to regulate iNOS induction and activity, we evaluated the effect of a neutralizing mAb to IL-10 on CD23-induced iNOS activity and nitrite production by CD23-bearing macrophages and found that both were significantly enhanced. Furthermore, the addition of exogenous IL-10 suppressed CD23-driven iNOS mRNA expression, iNOS activity and production of nitrite. These data suggest that, after CD23-ligation at the cell surface of human phagocytes, the secretion of IL-10 downregulates the CD23-induced NO production at the transcriptional level, thus providing an efficient feed-back mechanism.

Summary 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.

In the process of identification of the multiple endocrine neoplasia type 1 gene, which was recently published, we isolated a novel gene in the 11q13 region. This gene (named ZFPL1, for zinc-finger protein-like 1) is expressed strongly in the exocrine pancreas as a 1.4-kb polyadenylated RNA encoding a putative protein of 310 amino acids. A mouse EST contig predicts an equally sized murine protein with 91% amino acid sequence identity to the human protein. No significant homology with known proteins could be found through database screening. However, zinc-finger-like domains and leucine-zipper-like motifs in the predicted ZFPL1 protein were identified, suggesting the presence of DNA-binding and dimerization domains possibly involved in transcription regulation. This notion is supported by the presence of a putative bipartite nuclear localization signal. This paper presents the full-length cDNA sequence for this gene, its genomic structure and chromosomal orientation, and expression studies by Northern blot hybridization and RNA in situ hybridization.