Search

Multiple endocrine neoplasia type 1 (MEN1) is a rare syndrome characterized by the co-occurrence of primary hyperparathyroidism, duodenopancreatic neuroendocrine tumours (NETs) and/or pituitary adenomas. MEN1 can predispose patients to other endocrine and non-endocrine tumours, such as cutaneous tumours, central nervous system tumours and breast cancer. Endocrine tumours in patients with MEN1 differ from sporadic tumours in that they have a younger age at onset, present as multiple tumours in the same organ and have a different clinical course. Therefore, patients with overt MEN1 and those who carry a MEN1mutation should be offered tailored biochemical and imaging screening to detect tumours and evaluate their progression over time. Fortunately, over the past 10 years, knowledge about the clinical phenotype of these tumours has markedly progressed, thanks to the implementation of national registries, particularly in France and the Netherlands. This Review provides an update on the clinical management of MEN1-related tumours. Epidemiology, the clinical picture, diagnostic work-up and the main lines of treatment for MEN1-related tumours are summarized. Controversial therapeutic aspects and issues that still need to be addressed are also discussed. Moreover, special attention is given to MEN1 manifestations in children and adolescents.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by mutations in the MEN1 gene characterized by a broad spectrum of clinical manifestations, of which the most frequent are primary hyperparathyroidism, pituitary adenomas, and neuroendocrine tumors.

BackgroundUveitis is a frequent and early feature of sarcoidosis. As BTNL2 (butyrophilin-like 2) gene polymorphism was found linked with the susceptibility to sarcoidosis, we investigated whether a specific genotype of BTNL2 gene G16071A (or rs2076530) single-nucleotide polymorphism (SNP) would be associated with the risk of sarcoid uveitis in all patient subgroups.MethodsThe study compared the genotype frequencies of SNP G16071A of 135 patients with sarcoid uveitis (Sa+Uv+) with those of 196 patients with sarcoidosis without uveitis (Sa+Uv−), 81 patients with uveitis without sarcoidosis (Sa−Uv+), and 271 controls with no sarcoidosis nor uveitis (Sa−Uv−). Three hypothetical subgroups of patients with sarcoid uveitis (Sa+Uv+cases) were considered: (1) subgroup I: patients aged <45 years of both sexes and all ethnic origins; (2) subgroup II: Caucasian women aged >45 years; and (3) subgroup III: all other patients.ResultsA statistically significant difference in genotype frequencies was found between the groups Sa+Uv−and Sa−Uv−(p=3.2×10−6) and between the groups Sa+Uv+and Sa+Uv−(p=7.1×10−3). There was no difference between the three subgroups of Sa+Uv+patients. There was a statistically significant difference in genotype frequencies between Sa+Uv−and Sa+Uv+subgroup II (p=0.005) but no difference between Sa+Uv−and Sa+Uv+subgroup I.ConclusionNo association was found between G16071A and the susceptibility to sarcoid uveitis. BTNL2 gene G16071A SNP seems to be a predisposing factor for sarcoidosis except in Caucasian postmenopausal women with sarcoid uveitis in whom the GG genotype prevails. These and future results will help in understanding differences between particular subgroups of patients with sarcoid uveitis.

Supplemental Digital Content is available in the text.Methyl-CpG-binding protein 2 (MECP2) deleterious variants, which are responsible for Rett syndrome in girls, are involved in a wide spectrum of developmental disabilities in males. A neuropsychiatric phenotype without intellectual disability is uncommon in patients with MECP2deleterious variants. We report on two dizygotic twins with an MECP2-related psychiatric disorder without intellectual disability. Neuropsychological and psychiatric phenotype assessments were performed, and a genetic analysis was carried out. Both patients fulfilled the Pervasive Developmental Disorder criteria on Autism Diagnostic Observation Schedule and Asperger syndrome criteria on Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV). One patient developed early-onset schizophrenia (DSM-IV criteria) with two acute psychotic episodes, the latest one following corticosteroids and sodium valproate intake, with major hyperammonemia. A novel MECP2gene transversion c.491 G>T [p.(Ser164Ile)] was found in both twins. Pathogenicity of this variant was considered on the basis of strong clinical and molecular data. The underlying molecular basis of neuropsychiatric disorders may have important consequences on genetic counseling and therapeutic strategies.

Lynch syndrome is due to germline mutations in mismatch repair genes: MLH1, MSH2, MSH6and 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 PREMM1,2,6could 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 MMRgenes 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 PREMM1,2,6should 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.

Multiple Endocrine Neoplasia Type 1 (MEN1) is an autosomal dominant inherited syndrome, related to mutations in the MEN1gene. Controversial data suggest that the nonsynonymous p.Ala541Thr variant, usually considered as a non-pathogenic polymorphism, may be associated with an increased risk of MEN1-related lesions in carriers.

Purpose: Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by arteriovenous malformations (AVM), mostly cutaneous and mucous (telangiectases), but also involving the lungs (PAVM), liver (HAVM) and brain (CAVM). We studied the relationship between the phenotype and genotype in patients with a proven mutation in either ENG (HHT1) or ACVRL1 (HHT2).Methods: Clinical features and their age of onset were compared between HHT1 and HHT2. The type of mutation was also analyzed. Clinical manifestations were distinguished from lesions found by screening.Results: Ninety-three HHT1 patients and 250 HHT2 patients were included. Epistaxis occurred later in HHT2, with incomplete penetrance (P < 0.0001). Symptomatic PAVMs were more frequent in HHT1 (34.4 vs. 5.2%, P < 0.001), as were cerebral abscesses (7.5 vs. 0.8%, P = 0.002). Gastrointestinal bleeding occurred more frequently in HHT2 (16.4 vs. 6.5%, P = 0.017). Symptomatic hepatic involvement was only seen in HHT2 patients. PAVMs were more frequently detected in asymptomatic HHT1 patients (54 vs. 12.8%, P < 0.0001). PAVMs and HAVMs were often family clustered in HHT1 and HHT2, respectively. Truncating mutations were associated with a higher frequency of epistaxis and telangiectasis, in HHT2.Conclusion: This study shows major differences between HHT1 and HHT2 phenotypes, which should be taken into account for future clinical studies.

The identification of mutations in the MEN1gene causing MEN1 has represented a challenge since the cloning of the gene in 1997 because of the lack of mutation hot-spots in the gene and the lack of phenotype–genotype correlations. The use of denaturing high performance liquid chromatography (DHPLC), a high throughput, reliable and automated heteroduplex-based technique, is the ideal for mutation detection in MEN1. In this work, DHPLC was optimised for the screening of the nine coding exons and splice junctions of MEN1. Thanks to collaboration between two French laboratories recognised as reference centres for genotypic MEN1 diagnosis (Lyon and Lille), a blind retrospective study conducted in a cohort of 160 unrelated MEN1 probands with (or without) known germline mutations was undertaken to evaluate the sensitivity of DHPLC. We were able to detect 101 different sequence variations by DHPLC, distributed in the 10 analysed DNA fragments and corresponding to 100% of mutation detection compared with direct sequencing. 1·2% of samples were considered as false positive, exhibiting a heterogenous profile. DHPLC did not detect five cases of deletion or duplication of complete exons, neither did direct sequencing, showing the limits of the technique. Nevertheless, the method appeared to allow automated, rapid and low-cost mutation detection with high accuracy. Direct sequencing can be then applied to identify the sequence variations on the targeted DNA fragments showing heterozygous profile by DHPLC. In conclusion, genotypic diagnosis of MEN1can benefit from DHPLC in terms of efficacy, rapidity and cost.

FRAXE is a second locus associated with X chromosome fragility. Similar to FRAXA, the common mutation is a GCC expansion located in the 5′ untranslated region, leading to the hypermethylation of the region and to the subsequent inactivation of specific genes (FMR1 and FMR2, respectively). Unlike FRAXA, FRAXE has a rare occurrence and is less currently studied in routine analyses. The phenotype associated with FRAXE is usually considered as mild or moderate mental retardation, with incomplete penetrance. However, phenotypegenotype relations have been less characterized.

The French and Belgian GENEM study group’s multiple endocrine neoplasia type I (MEN-I) database was used to evaluate trends in clinical presentation, surgical treatment of primary hyperparathyroidism (pHPT) (n=245), and prognostic factors for hypercalcemia correction among 256 MEN-I cases. The patients were retrieved through the GENEM network from various Belgian and French instititutions with the help of genetics laboratories. Among the 245 pHPT patients (96%), 42% were men. The mean age at the time of diagnosis was 39.5 ± 13.3 years. Trends were studied for three periods: before 1986, from 1986 to 1990, and thereafter. After 1990 MEN-I patients were more often diagnosed with isolated pHPT (8%, 11%, 28%, for the three periods, respectively; p=0.002); it was seen more often in screened patients (31%, 28%, 53%; p=0.001), more often among those in already known MEN-I families (64%, 45%, 72%; p=0.005), and among those with lower preoperative calcemia (2.93, 2.87, 2.79 mmol/L; p=0.001). The age at pHPT diagnosis remained constant throughout the study. The percentage of cervical explorations dropped during the entire study (87%, 87%, 53%; p<0.0001). After 1985 the percentage of subtotal parathyroidectomies increased (25%, 59%, 51%; p=0.0004). Pathology disclosed more hyperplasias (59%, 85%, 74%; p=0.008). Postoperative hypercalcemia decreased (47%, 15%, 19%; p<0.0001); and postoperative hypocalcemia increased nonsignificantly (5%, 15%, 15%; p=0.1). Subtotal parathyroidectomy [odds ratio (OR) 13], no MEN-I family background (OR 3), and the most recent study period (>1985) (OR 3) were significant predictive factors of hypercalcemia correction according to the multivariate analysis. This is the first multicentric study on the management of MEN-I-related pHPT. Immediate postoperative hHPT cure increased, but only 80% of the operated patients were cured after 1990. Fifteen percent were hypocalcemic. Because MEN-I-related hHPT cure remains difficult to achieve, we advocate that subtotal parathyroidectomies be performed in specialized centers. Introduction. A partir de 245 cas d’hyperparathyroïdie (pHPT) enregistrés au groupe d’étude franco-belge du GENEM (96%), (256 cas de NEM1), on a analysé l’évolution de la présentation clinique, le résultat après traitement chirurgical et de son effet sur la maladie pHPT. Population et méthodes. Les patients ont été retrouvés grâce au réseau multicentrique du GENEM et avec l’aide des laboratoires d’analyse génétique. Parmi les 245 cas de pHPT, 42% étaient des hommes. L’âge moyen au moment du diagnostic a été de 39,5 ± 13,3 ans. Trois périodes ont été étudiées: avant 1986, de 1986 à 1990, et après 1990. Résultats. Après 1990, il s’agissait plus souvent d’pHPT isolées (8%-11%-28%, 0; p=0,002), plus souvent dépistées (31%-28%-53%, p=0,001), plus souvent au sein de familles NEM1 connues (64%-45%-72%, respectivement: p=0,005), et avec une calcémie plus basse (2,93-2,87-2,79, respectivement; mmol/L, p=0,001). L’âge au moment du diagnostic de pHPT n’a pas changé au cours du temps. Le pourcentage de patients opérés pour exploration cervicale a diminué (87%-87%-53%, respectivement; p<0,0001). Après 1985, le pourcentage de parathyroïdectomies subtotales a augmenté (25%-59%-51%, respectivement: p=0,0004). L’anatomo-pathologie a mis en évidence plus d’hyperplasies (59%-85%-74%, respectivement; p=0,008). L’hypercalcémie post-opératoire a diminué (47%-15%-19%, respectivement; p<0,0001) et l’hypocalcémie a augmenté non significativement (5%-5% – 15%, respectivement; p=0,1). La parathyroïdectomie subtotale (Odds ratio=13), l’absence d’autre atteinte familiale (Odds ratio=3), et la prise en charge après 1985 (Odds ratio=3) ont été les facteurs indépendants prédictifs d’un contrôle de la pHPT en analyse multivariée. Conclusion. Il s’agit de la première analyse multicentrique de la prise en charge de la pHPT des NEM1. Après 1990, la correction de la pHPT a été plus efficace mais seulement dans 80% des cas. Quinze pourcent des patients étaient hypocalcémiques. Ces constatations poussent à opérer les pHPT des NEM1 en centres spécialisés pour réaliser une parathyroïdectomie subtotale. Introducción: Se utilizó, para analizar los casos de hiperparatiroidismo (pHPT) (n=245) registrados como MEN L (n=256), el grupo de estudio franco-belga del GENEM. Se analizaron: La evolución clinica y el tratamiento quirúrgico y, sus efectos sobre la pHPT. Material y métodos: Los pacientes se descubrieron gracias a la red multicéntrica del GENEM y con la ayuda de laboratorios de análisis genético. Entre los 245 pHPT (96%), 42% eran varones. La edad media, en el momento del diagnóstico, fue de 39.5 ± 13.3 años. Su evolución se estudió en tres periodos de tiempo: antes de 1986, entre 1986 y 1990 y después de 1990. Resultados: Después de 1990 los casos de MEN 1 se diagnosticaron sobre todo por determinaciones aislada de pHPT (8%-11%-28%, p=0.002), se descubrieron con más frecuencia (31%-28%-53%, p=0.001), en especial en el seno de familias conocidas por padecer un MEN 1 (64%-45%-72%, p=0.005) y con calcemias más bajas (2.93-2.87-2.79 mmol/L, p=0.001). La edad, al efectuar el diagnóstico, no se ha modificado a lo largo del tiempo. El porcentaje de enfermos operados ha disminuido (87%-87%-53%, p<0.0001). A partir de 1985 el porcentaje de paratiroidectomias subtotales aumentó (25%-59%-51%, p=0.0004). Los estudios anatomopatológicos revelaron una mayor incidencia de hiperplasias (59%-85% -74%, p=0.008). La hipercalcemia postoperatoria ha disminuido (47%-15%-19%, p<0.0001) y la hipocalcemia aumentado, pero no significativamente (5%-5%-15%, p=0.1). En un análisis multivariante la paratiroidectomia subtotal (Odds ratio=13), la falta de antecedentes familiares de MEN 1 (Odds ratio=3) y la operación más precoz a partir de 1985 (Odds ratio=3), son los factores predictivos más significantes de la corrección de la hipercalcemia. Conclusión: Se trata del primer análisis multicéntrico del tratamiento del sÍndrome de MEN 1 referido a la pHPT. La curación del hHPT aumentó en el postoperatorio inmediato, pero sólo el 80% de los pacientes operados estaban curados después de 1990. 15% de los pacientes estaban hipocalcémicos. Dado que la curación de enfermos con síndrome de MEN 1 relacionado con hHPT es dificil, se aconseja realizar una paratiroidectomía subtotal en centros especializados.

The French and Belgian GENEM study group’s multiple endocrine neoplasia type I (MEN-I) database was used to evaluate trends in clinical presentation, surgical treatment of primary hyperparathyroidism (pHPT) (n=245), and prognostic factors for hypercalcemia correction among 256 MEN-I cases. The patients were retrieved through the GENEM network from various Belgian and French instititutions with the help of genetics laboratories. Among the 245 pHPT patients (96%), 42% were men. The mean age at the time of diagnosis was 39.5 ± 13.3 years. Trends were studied for three periods: before 1986, from 1986 to 1990, and thereafter. After 1990 MEN-I patients were more often diagnosed with isolated pHPT (8%, 11%, 28%, for the three periods, respectively; p=0.002); it was seen more often in screened patients (31%, 28%, 53%; p=0.001), more often among those in already known MEN-I families (64%, 45%, 72%; p=0.005), and among those with lower preoperative calcemia (2.93, 2.87, 2.79 mmol/L; p=0.001). The age at pHPT diagnosis remained constant throughout the study. The percentage of cervical explorations dropped during the entire study (87%, 87%, 53%; p<0.0001). After 1985 the percentage of subtotal parathyroidectomies increased (25%, 59%, 51%; p=0.0004). Pathology disclosed more hyperplasias (59%, 85%, 74%; p=0.008). Postoperative hypercalcemia decreased (47%, 15%, 19%; p<0.0001); and postoperative hypocalcemia increased nonsignificantly (5%, 15%, 15%; p=0.1). Subtotal parathyroidectomy [odds ratio (OR) 13], no MEN-I family background (OR 3), and the most recent study period (>1985) (OR 3) were significant predictive factors of hypercalcemia correction according to the multivariate analysis. This is the first multicentric study on the management of MEN-I-related pHPT. Immediate postoperative hHPT cure increased, but only 80% of the operated patients were cured after 1990. Fifteen percent were hypocalcemic. Because MEN-I-related hHPT cure remains difficult to achieve, we advocate that subtotal parathyroidectomies be performed in specialized centers.

Multiple endocrine neoplasia type 1 (MEN 1) is a familial cancer syndrome associated primarily with endocrine tumors of the parathyroids, enteropancreas and anterior pituitary. However, tumors of mesenchymal origin such as angiofibroma and collagenoma of the skin have also been associated with the syndrome. This highlights the possibility of an association between MEN 1 and some other types of tumors. Here we report 7 cases of primary malignant melanoma occurring in 7 MEN 1 families, all patients exhibiting classic features of MEN 1. Based on these findings and the previous implication of multiple melanoma tumor suppressor(s) in 11q, including the MEN1 region, we have investigated the involvement of the MEN1 gene in melanoma tumorigenesis. Mutation analysis was performed on a panel of 39 sporadic metastatic melanomas, 13 melanoma cell lines and 20 melanoma families without CDKN2A or CDK4 germline mutations. In addition, 19 sporadic metastatic tumors were screened for loss of heterozygosity (LOH) in 11q13. LOH was detected in 6 tumors (32%), and in 4 of the tumors the pattern of LOH suggested that the deletion included the MEN1 gene locus. A novel somatic nonsense mutation in exon 7 (Q349X) was identified in 1 sporadic tumor which also showed loss of the wild-type allele. We conclude that the MEN1 gene plays a role in the tumorigenesis of a small subgroup of melanoma. Int. J. Cancer 87:463–467, 2000. © 2000 Wiley-Liss, Inc.

We have investigated the endogenous expression of menin, a protein encoded by the gene mutated in multiple endocrine neoplasia type 1 (MEN1). Western blot analysis showed strong expression of menin as a 68 kDa protein in all of 7 human and primate cell lines tested. In a panel of 12 fetal human tissue extracts, 68 kDa menin was readily detected in brain cortex, kidney, pituitary, testis and thymus and weakly detected in thyroid. Reproducible bands other than 68 kDa were observed in adrenal and heart, whereas menin was undetectable in liver, lung, pancreas and skin. Analysis of synchronized HeLa cells revealed no variation in the amount or size of menin throughout the cell cycle. Protein expression was compared between lymphoblastoid cell lines from healthy controls and MEN1 patients carrying nonsense mutations on 1 allele. No truncated protein was detected in either cytoplasmic or nuclear fractions in mutation-carrying cells. The expression level and cellular location of full-length menin did not differ between cell lines derived from MEN1 patients and healthy donors. This suggests that the wild-type allele has been up-regulated in mutation-carrying cells to compensate for the loss of 1 functional allele. Int. J. Cancer 85:877–881, 2000. © 2000 Wiley-Liss, Inc.

Lymphocyte function-associated antigens 1 and 3 (LFA-1. LFA-3) and intercellular adhesion molecule 1 (ICAM-1) are cell surface adhesion molecules necessary for immune processes requiring intercellular contact. It was recently proposed that malignant Burkitt's lymphoma cells (BL) may escape from immunosurveillance through the downregulation of LFA-1 (CD11a/CD18) or LFA-3 (CD58) and ICAM-1 (CD54) molecules. Expression of these three adhesion antigens was investigated in 19 BL lines. LFA-1 or LFA-3 expression was found to be absent or low in 8 of 11 Epstein-Barr virus (EBV) genome positive BL, but strongly expressed on all nonmalignant EBV genome positive lym-phoblastoid cell lines (LCL). Negative or weak expression of LFA-1 and LFA-3 was also observed in 7 of 8 EBV genome negative BL. ICAM-1 was found to be expressed on the cell surface of the majority of BL lines. BL lines growing as individual cells did not express LFA-1, whereas clump-forming BL lines expressed this marker involved in B-cell homotypic aggregation. Expression of LFA-1 and LFA-3 was induced on in vitro infection of EBV-negative BL cells with the immortalizing EBV strain B95-8, and weakly with the nonimmortalizing EBV strain P3HR1. EBNA2 and LMP, two EBV encoded proteins expressed in LCL and in BL infected with B95-8 (BL/B95-8), are not expressed in P3HR1 infected BL cells (BL/P3HR1). Stable expression of EBNA2 after gene transfer in a BL/P3HR1 cell line did not restore the level of LFA-1 and LFA-3 found on BL/B95-8 cells. In EBV-positive BL cells expressing LFA-1 and LFA-3. LMP was found coexpressed, supporting the recent finding of the role of LMP in B-cell adhesion receptor activation. Consequently, diminished LFA-1 and LFA-3 expression appears to be a common characteristic of numerous EBV-positive BL as well as EBV-negative BL. These findings are discussed in the framework of BL pathogenesis.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant familial cancer syndrome characterized by parathyroid, pancreatic, and anterior pituitary tumors. The MEN1 locus has been previously localized to chromosome 11q13, and a 2-Mb gene-rich region flanked by D11S1883 and D11S449 has been defined. We have pursued studies to facilitate identification of the MEN1 gene by narrowing this critical region to a 900-kb interval between the VRF and D11S1783 loci through meiotic mapping. This was achieved by investigating 17 cosmids for microsatellite polymorphisms, which defined two novel polymorphisms at the VRF and A0138 loci, and utilizing these to characterize recombinants in MEN1 families. In addition, we have established a 1200-kb sequence-ready contig consisting of 26 cosmids, eight BACs, and eight PACs that encompass this region. The precise locations for 19 genes and three ESTs within this contig have been determined, and three gene clusters consisting of a centromeric group (VRF, FKBP2, PNG, and PLCB3), a middle group (PYGM, ZFM1, SCG1, SCG2 (which proved to be the MEN1 gene), and PPP2R5B), and a telomeric group (H4B, ANG3, ANG2, ANG1, FON, FAU, NOF, NON, and D11S2196E) were observed. These results represent a valuable transcriptional map of chromosome 11q13 that will help in the search for disease genes in this region.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder with a high penetrance characterized by tumors of the parathyroid glands, the endocrine pancreas, and the anterior pituitary. TheMEN1gene, a putative tumor suppressor gene, has been mapped to a 3- to 8-cM region in chromosome 11q13 but it remains elusive as yet. We have combined the efforts and resources from four laboratories to form the European Consortium on MEN1 with the aims of establishing the genetic and the physical maps of 11q13 and of further narrowing the MEN1 region. A 5-Mb integrated map of the region was established by fluorescencein situhybridization on both metaphase chromosomes and DNA fibers, by hybridization to DNA from somatic cell hybrids containing various parts of human chromosome 11, by long-range restriction mapping, and by characterization of YACs and cosmids. Polymorphic markers were positioned and ordered by physical mapping and genetic linkage in 86 MEN1 families with 452 affected individuals. Two critical recombinants identified in two affected cases placed theMEN1gene in an ≈2-Mb region aroundPYGM,flanked by D11S1883 and D11S449.

Primary hyperparathyroidism (P-HPT) is a common disease whose prevalence has been estimated at between 1 per 1000 and 1 per 2000. Approximately 80–90% of the patients with P-HPT have a single gland adenoma and are sporadic cases. The remaining 10–20% of patients with P-HPT have a hyperplasia and/or adenoma involving two or more glands, and most of such cases occur with familial aggregation (1). Primary HPT is rarely related to a parathyroid carcinoma. In all cases, diagnosis is mainly based on biological criteria, such hypercalcemia (evaluated on total and ionized serum calcium), elevated circulating levels of parathormone (PTH), increased level of urinary calcium excretion and hypophosphoremia. In a few cases, diagnosis is related to classical clinical manifestations of chronic hypercalcemia, such as bone or stone disease, neuromuscular or gastrointestinal signs, or malignant hypercalcemia. The major goals in management of patients are, firstly, the prevention of obvious effects of chronic and

Benlian P, Giraud S, Lahlou N, Roger M, Blin C, Holler C, Lenoir G, Sallandre J, Calender A, Turpin G. Familial acromegaly: a specific clinical entity. Eur J Endocrinol 1995;133:451–6. ISSN 0804–4643Familial acromegaly is a very rare inherited disorder, characterized by the clustering within a single family of several related cases with somatotroph adenomas and acromegaly. The causes of these dominantly inherited pituitary tumours remain unknown. Although these families have a clinical presentation distinct from that of multiple endocrine neoplasia type 1 (MEN-1), the question of this syndrome as being linked to the MEN-1 locus has remained open. Our aim was to study a three-generation family with cases of acromegaly in a mother and her son, to explore better the clinical presentation of the disease, its pattern of inheritance and to test the hypothesis of a genetic linkage to the MEN-1 locus using closely linked polymorphic genetic markers. The refined analysis of 15 unaffected relatives revealed miscellaneous non-specific endocrine dysfunctions and the presence of multiple lipomata, as noted previously in some cases. Moreover, the notion of acromegalo-gigantism in the maternal grandmother and an incomplete penetrance appeared even more typical, suggesting that familial acromegaly is a specific clinical entity. Finally, under the hypotheses assumed for segregation analysis, no clinical, biological or genetic evidence of linkage to the MEN-1 locus could be retained in this family. However, these conclusions were limited because of incomplete penetrance and uncertain definition of the carrier status. Therefore, we conclude that further identification of the genetic predisposition to familial acromegaly might be obtained from the combined molecular genetic analysis of several families presenting with the same clinical features.Pascale Benlian, Service d'Endocrinologie Métabolisme, Groupe Hospitalier Pitié Salpétrière, 83 Boulevard de l'Hôpital, 75651 Paris cedex 13, France

Abstract.: Apoptosis in murine myeloid cell lines requires the expression of the Requiem gene, which encodes a putative zinc finger protein. We detected the protein in both cytoplasmic and nuclear subcellular fractions of murine myeloid cells and human K562 leukemia cells, which suggests that the protein might have a function distinct from a transcription factor. This distribution did not alter upon apoptosis induction by IL-3 deprivation. As an approach to investigate its role in development, we determined the spatio-temporal expression pattern in the mouse. Expression was detected in various tissues in earlier gestational age; however, confined to testes, spleen, thymus, and part of the hippocampus in the adult mouse. The expression profile is consistent with a functional role during rapid growth and cell turnover, and in agreement with a regulatory function for hematopoietic cells. The human cDNA clone sequenced showed high homology to its murine counterpart and extended the open reading frame by 20 codons upstream. The gene is located in the proximal region of mouse Chromosome (Chr) 19. In the homologous human region at 11q13, it is located at about 150 kb centromeric from MLK3.

No relevant conflicts of interest to declare.

Abstract 2336

Familial cases of carcinoid tumours that are not associated with any known syndrome or disease are extremely rare. All cases reported in the world literature have involved carcinoid tumours of the gastrointestinal tract. Two cases of carcinoid tumours of the small intestine in a father and daughter are presented. Laboratory analyses did not support the hypothesis that the occurrence of carcinoid tumours in this family is a variant of the multiple endocrine neoplasia type 1 syndrome. A review of the literature on familial occurrence of intestinal carcinoid tumours in the absence of any other known carcinoid tumour-predisposing genetic syndrome is provided.