Beyond MEN1, When to Think About MEN4? Retrospective Study on 5600 Patients in the French Population and Literature Review.

CONTEXT: Germline CDKN1B variants predispose patients to multiple endocrine neoplasia type 4 (MEN4), a rare MEN1-like syndrome, with <100 reported cases since its discovery in 2006. Although CDKN1B mutations are frequently suggested to explain cases of genetically negative MEN1, the prevalence and phenotype of MEN4 patients is poorly known, and genetic counseling is unclear. OBJECTIVE: To evaluate the prevalence of MEN4 in MEN1-suspected patients and characterize the phenotype of MEN4 patients. DESIGN: Retrospective observational nationwide study. Narrative review of literature and variant class reassessment. PATIENTS: We included all adult patients with class 3/4/5 CDKN1B variants identified by the laboratories from the French Oncogenetic Network on Neuroendocrine Tumors network between 2015 and 2022 through germline genetic testing for MEN1 suspicion. After class reassessment, we compared the phenotype of symptomatic patients with class 4/5 CDKN1B variants (ie, with genetically confirmed MEN4 diagnosis) in our series and in literature with 66 matched MEN1 patients from the UMD-MEN1 database. RESULTS: From 5600 MEN1-suspected patients analyzed, 4 with class 4/5 CDKN1B variant were found (0.07%). They presented with multiple duodenal NET, primary hyperparathyroidism (PHPT) and adrenal nodule, isolated PHPT, PHPT, and pancreatic neuroendocrine tumor. We listed 29 patients with CDKN1B class 4/5 variants from the literature. Compared with matched MEN1 patients, MEN4 patients presented lower NET incidence and older age at PHPT diagnosis. CONCLUSION: The prevalence of MEN4 is low. PHPT and pituitary adenoma represent the main associated lesions, NETs are rare. Our results suggest a milder and later phenotype than in MEN1. Our observations will help to improve genetic counseling and management of MEN4 families.

Social, neurodevelopmental, endocrine, and head size differences associated with atypical deletions in Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) is a multisystem disorder caused by a hemizygous deletion on 7q11.23 encompassing 26-28 genes. An estimated 2-5% of patients have "atypical" deletions, which extend in the centromeric and/or telomeric direction from the WBS critical region. To elucidate clinical differentiators among these deletion types, we evaluated 10 individuals with atypical deletions in our cohort and 17 individuals with similarly classified deletions previously described in the literature. Larger deletions in either direction often led to more severe developmental delays, while deletions containing MAGI2 were associated with infantile spasms and seizures in patients. In addition, head size was notably smaller in those with centromeric deletions including AUTS2. Because children with atypical deletions were noted to be less socially engaged, we additionally sought to determine how atypical deletions relate to social phenotypes. Using the Social Responsiveness Scale-2, raters scored individuals with atypical deletions as having different social characteristics to those with typical WBS deletions (p = .001), with higher (more impaired) scores for social motivation (p = .005) in the atypical deletion group. In recognizing these distinctions, physicians can better identify patients, including those who may already carry a clinical or FISH WBS diagnosis, who may benefit from additional molecular evaluation, screening, and therapy. In addition to the clinical findings, we note mild endocrine findings distinct from those typically seen in WBS in several patients with telomeric deletions that included POR. Further study in additional telomeric deletion cases will be needed to confirm this observation.

Single Centre Experience in Patients with Primary Hyperparathyroidism: Sporadic, Lithium-associated and in Multiple Endocrine Neoplasia.

PURPOSE: It is assumed that primary hyperparathyroidism (pHPT) in Multiple Endocrine Neoplasia (MEN) and lithium-associated pHPT (LIHPT) are associated with multiple gland disease (MGD), persistence and recurrence. The studies purpose was to determine frequencies, clinical presentation and outcome of sporadic pHPT (spHPT), LIHPT and pHPT in MEN. Additional main outcome measures were the rates of MGD and persistence/recurrence. METHODS: Retrospective analysis of medical records of 682 patients with pHPT who had attended the University Hospital of Marburg between 01-01-2004 and 30-06-2013. All patients were sent a questionnaire asking about their history of lithium medication. RESULTS: Out of 682 patients, 557 underwent primary surgery (532 spHPT, 5 LIHPT, 20 MEN), 38 redo-surgery (31 spHPT, 7 MEN), 55 were in follow-up due to previous surgery (16 spHPT, 1 LIHPT, 38 MEN) and 37 were not operated (33 spHPT, 1 LIHPT, 3 MEN). Primary surgeries were successful in 97.4%, revealed singular adenomas in 92.4%, double adenomas in 2.9% and MGD in 3.4% of the cases. Rates of MGD in MEN1 (82.35%) were significantly higher than in spHPT (3.8%), while there was no significant difference between LIHPT (20%) and spHPT. Rates of persistence/recurrence did not significantly differ due to type of surgery (bilateral/unilateral) or type of HPT (spHPT/LIHPT/MEN). CONCLUSIONS: History of lithium medication is rare among pHPT patients. While MGD is common in MEN1, rates of MGD, persistence or recurrence in LIHPT were not significantly higher than in spHPT.

Hiperparatiroidismo primario asociado a neoplasia endocrina múltiple tipo 1 (MEN 1). Experiencia en 71 casos / Primary hyperparathyroidism associated with MEN 1: Experience in 71 cases

INTRODUCCIÓN: El hiperparatiroidismo (HPT) asociado al MEN 1 se caracteriza por ser una afectación multiglandular, no afectándose todas las glándulas en el mismo momento. Suele ser asintomático, aunque la afectación ósea es elevada en los pacientes jóvenes. Las tasa de recidiva y persistencias es de 25-35%. Los objetivos fueron: a) estudiar HPT-MEN 1; y b) analizar las variables relacionadas con la presencia o no de clínica y con la persitencia. MÉTODO: De 97 sujetos con MEN 1 diagnosticados en el HUVA, Murcia, pertenecientes a 16 familias, se han estudiado restrospectivamente 71 pacientes con afectación paratiroidea. Las variables estudiadas son: mutación, edad de diagnóstico, clínica, los valores de calcio, fóforo y PTHi, MIBI, técnica quirúrgica, valores de la PTHi y tasa de recidiva. RESULTADOS: La edad media fue de 38 años, y 50 estaban asintomáticos en el momento del diagnóstico. La técnica quirúgica realizada fue: paratiroidectomía subtotal (n = 55), paratiroidectomía de 3 glándulas (n = 7) y resección de menos de 3 glándulas (n = 9). Se asoció timectomía transcervical en 53. El seguimiento medio ha sido de 102,9 meses. Se han encontrado 21 recidivas (10 cirugía incompleta). Encontramos una relación estadísticamente significativa entre: la edad de diagnóstico (p < 0,0005) y los valores elevados de calcio (p < 0,008) y la presencia de clínica en el momento del diagnóstico, la técnica quirúrgica incompleta (p < 0,003), no timectomía (p < 0,0001) y seguimiento (p < 0,001) y la recidiva tras la cirugía. CONCLUSIÓN: La realización de screening genético y clínico nos permite un diagnóstico en fase asintomática y tratamiento precoz, evitando así complicaciones secundarias a la evolución del HPT. La tasa de recidiva del HPT en el MEN 1 es elevada, siendo los factores de recidiva el tiempo de seguimiento y la técnica quirúrgica realizada

INTRODUCTION: Primary hyperparathyroidism (pHPT) in MEN 1 is characterized by multiglandular disease and early involvement of parathyroid glands at different times. Persistence and recurrence range from 25%-35%. The purpose was: a) to describe the experience and the treatment of patients with pHPT in MEN 1; b) to analyze the variables related with clinical presentation and recurrence. METHOD: A total of 97 patients with MEN 1 were diagnosed in a tertiary hospital. A retrospective analysis was made in patients with pHPT (n = 71). Study variables: age at diagnosis, mutation, clinical presentation, laboratory tests, surgical technique, and recurrence of HPT. RESULTS: Mean age was 38 years, and 50 patients were asymptomatic. The surgical technique was: subtotal parathyroidectomy (n = 55), resection of three glands (n = 7), and resection of less glands (n = 9). Transcervical thymectomy was performed in 53 patients. Mean follow-up was 102.9 months. There were 21 recurrences, There were correlations between age at diagnosis and serum calcium levels with the presence of symptoms (P < .0001). There were also correlations between recurrence and surgical technique (P < .03), non-association with thymectomy (P < .0001), and follow-up time (P < .03). CONCLUSION: Performing genetic and clinical screening allows us to make a diagnosis in the asymptomatic period and to provide early treatment for HPT in MEN 1. The recurrence rate is high, and follow-up time and the surgical technique used are risk factors for recurrence

Hiperparatiroidismo primario / Primary hyperparathyroidism

El hiperparatiroidismo primario (HPP) es una enfermedad endocrinológica frecuente, caracterizada por una secreción excesiva de hormona paratiroidea (PTH) que produce generalmente hipercalcemia y un conjunto de manifestaciones clínicas variables. Las manifestaciones específicas son la nefrolitiasis y la osteítis fibrosa quística, que caracterizan el fenotipo clásico de la enfermedad. Sin embargo, en la actualidad la mayoría de los pacientes son diagnosticados de forma casual tras realizar una analítica de rutina. Asimismo, se ha descrito una nueva forma de presentación denominada HPP normocalcémico cuya repercusión clínica no se encuentra bien establecida. El perfil bioquímico del HPP se caracteriza por hipercalcemia y concentraciones de PTH elevadas o inapropiadamente normales. La paratiroidectomía es el único tratamiento definitivo para el HPP, aunque algunos pacientes no son candidatos a la cirugía o rechazan la intervención. El tratamiento médico con el calcimimético cinacalcet ha demostrado normalizar la calcemia en un elevado porcentaje de casos (AU)

Primary hyperparathyroidism (PHPT) is a common endocrinological process, characterized by chronic elevation of serum concentrations of calcium and parathyroid hormone (PTH). Many years ago, the most frequent forms of clinical presentation were symptomatic renal or skeletal disease with moderate or severe hypercalcemia; however, currently, most patients have few symptoms and mild hypercalcemia. A new form of presentation called normocalcemic PHPT has also been described but clinical consequences are not well established. The biochemical profile of PHPT is characterized by hypercalcemia and high or inappropriately normal PTH concentrations. Parathyroidectomy is the only definitive cure. Medical treatment with the calcimimetic cinacalcet has been shown to normalize calcemia in a high percentage of cases (AU)

Concurrent endocrine neoplasias in dogs and cats: a retrospective study (2004-2014).

Multiple endocrine neoplasia (MEN) is a well-known syndrome in human medicine, whereas only a few cases of concurrent endocrine neoplasias have been reported in dogs and cats. The aim of this study was to evaluate the prevalence of concurrent endocrine neoplasias in dogs and cats at our clinic, identify possible breed and sex predispositions and investigate similarities with MEN syndromes in humans. Postmortem reports of 951 dogs and 1155 cats that died or were euthanased at the Clinic for Small Animal Internal Medicine, University of Zurich, between 2004 and 2014 were reviewed, and animals with at least two concurrent endocrine neoplasias and/or hyperplasias were included. Twenty dogs and 15 cats met the inclusion criteria. In dogs, the adrenal glands were most commonly affected. Multiple tumours affecting the adrenal glands and the association of these tumours with pituitary adenomas were the most common tumour combinations. Only one dog had a combination resembling human MEN type 1 syndrome (pituitary adenoma and insulinoma). In cats, the thyroid glands were most commonly affected and there were no similarities to human MEN syndromes. The prevalence of concurrent endocrine neoplasia was 2.1 per cent in dogs and 1.3 per cent in cats and MEN-like syndromes are very rare in these species.

Multiple Endocrine Neoplasia and Hyperparathyroid-Jaw Tumor Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood.

Children and adolescents who present with neuroendocrine tumors are at extremely high likelihood of having an underlying germline predisposition for the multiple endocrine neoplasia (MEN) syndromes, including MEN1, MEN2A and MEN2B, MEN4, and hyperparathyroid-jaw tumor (HPT-JT) syndromes. Each of these autosomal dominant syndromes results from a specific germline mutation in unique genes: MEN1 is due to pathogenic MEN1 variants (11q13), MEN2A and MEN2B are due to pathogenic RET variants (10q11.21), MEN4 is due to pathogenic CDKN1B variants (12p13.1), and the HPT-JT syndrome is due to pathogenic CDC73 variants (1q25). Although each of these genetic syndromes share the presence of neuroendocrine tumors, each syndrome has a slightly different tumor spectrum with specific surveillance recommendations based upon tumor penetrance, including the age and location for which specific tumor types most commonly present. Although the recommended surveillance strategies for each syndrome contain similar approaches, important differences do exist among them. Therefore, it is important for caregivers of children and adolescents with these syndromes to become familiar with the unique diagnostic criteria for each syndrome, and also to be aware of the specific tumor screening and prophylactic surgery recommendations for each syndrome. Clin Cancer Res; 23(13); e123-e32. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.

Childhood neuroendocrine tumours: a descriptive study revealing clues for genetic predisposition.

BACKGROUND: Neuroendocrine tumours (NETs) are rare in children and limited data are available. We aimed to specify tumour and patient characteristics and to investigate the role of genetic predisposition in the aetiology of paediatric NETs. METHODS: Using the Dutch Pathology Registry PALGA, we collected patient- and tumour data of paediatric NETs in the Netherlands between 1991 and 2013 (N=483). RESULTS: The incidence of paediatric NETs in the Netherlands is 5.40 per one million per year. The majority of NETs were appendiceal tumours (N=441;91.3%). Additional surgery in appendiceal NETs was indicated in 89 patients, but performed in only 27 of these patients. Four out of five patients with pancreatic NETs were diagnosed with Von Hippel-Lindau disease (N=2) and Multiple Endocrine Neoplasia type 1 (N=2). In one patient with an appendiceal NET Familial Adenomatous Polyposis was diagnosed. On the basis of second primary tumours or other additional diagnoses, involvement of genetic predisposition was suggestive in several others. CONCLUSIONS: We identified a significant number of patients with a confirmed or suspected tumour predisposition syndrome and show that paediatric pancreatic NETs in particular are associated with genetic syndromes. In addition, we conclude that treatment guidelines for appendiceal paediatric NETs need revision and improved implementation.

Multiple Endocrine Neoplasia Syndromes: A Comprehensive Imaging Review.

MEN1, MEN2, and MEN4 comprise a series of familial disorders involving the simultaneous occurrence of tumors in more than one endocrine organ, collectively known as multiple endocrine neoplasia. Patients with this family of disorders develop tumors of the parathyroid gland, pancreas, pituitary gland, adrenal gland, and thyroid gland, along with miscellaneous neuroendocrine tumors of the respiratory and gastrointestinal tracts. Although some patients undergo early prophylactic surgical management, particularly in the setting of familial medullary thyroid carcinoma, many develop tumors later in life. These tumors are often discovered at imaging for screening purposes. Recognition of the imaging features of the known tumors is important for appropriate patient management.

Insulinoma: análisis multicéntrico y retrospectivo de la experiencia de 3 décadas (1983-2014) / Insulinoma: A multicenter, retrospective analysis of three decades of experience (1983-2014)

OBJETIVO: Analizar las características clínicas, metodología diagnóstica, tratamientos empleados y resultados de los casos de insulinoma diagnosticados y tratados entre 1983-2014 en 4 centros hospitalarios españoles. MÉTODOS: Se incluyeron en el estudio todos los pacientes que tenían demostración histológica de tumor secretor de insulina o criterios diagnósticos bioquímicos y morfológicos de insulinoma. RESULTADOS: Se estudiaron 29 pacientes (23 mujeres [79,3%]; edad media 48,7 ± 17,4 años [intervalo 16-74]). En 26 (89,7%) casos el tumor fue esporádico y en el resto (3 mujeres, 10,3%) se presentó en el contexto de una neoplasia endocrina múltiple tipo 1. Hubo 3 (10,3%) insulinomas múltiples, uno de ellos asociado a neoplasia endocrina múltiple tipo 1, y 2 (6,9%) insulinomas malignos, ambos esporádicos. La mayoría (n = 18, 62,1%) mostró hipoglucemia de ayuno, aproximadamente un tercio (31%) hipoglucemia tanto de ayuno como posprandial y el 6,9% solo hipoglucemia posprandial. El tiempo en alcanzar el nadir de glucosa (37,3 ± 6,5 mg/dl) en la prueba de ayuno fue 9,0 ± 4,4 h, con insulinemia de 25,0 ± 20,3 μU/ml. La TAC abdominal localizó el insulinoma en el 75% de los casos. El 93,1% (n = 27) de los pacientes fue intervenido quirúrgicamente (enucleación, 18 [66,7%] y pancreatectomía parcial, 9 [33,3%] pacientes; tamaño tumor 1,7 ± 0,7 cm). La cirugía consiguió la curación en la mayoría (n = 24, 88,9%) de los pacientes. CONCLUSIÓN: El insulinoma en nuestro medio es un tumor benigno, de pequeño tamaño y solitario, que afecta más a mujeres entre 45-50 años y que se localiza generalmente con TAC abdominal. La cirugía mediante enucleación constituye el método terapéutico más habitual consiguiendo unas altas tasas de curación

OBJECTIVE: To analyze the clinical features, diagnostic procedures, treatment, and clinical outcome of insulinomas diagnosed and treated in the period 1983-2014 in four Spanish hospitals. METHODS: All patients with either biochemical and morphological criteria of insulinoma and/or histological demonstration of insulin-secreting tumor were included. RESULTS: Twenty-nine patients [23 women (79.3%); mean age 48.7 ± 17.4 years (range, 16-74)] were recruited. Twenty-six patients (89.7%) had sporadic tumors, and the rest (3 women, 10.3%) developed in the context of multiple endocrine neoplasia type 1. There were 3 (10.3%) multiple insulinomas, one associated with multiple endocrine neoplasia type 1, and two (6.9%) malignant insulinomas, both sporadic. Most patients (n = 18, 62.1%) had fasting hypoglycemia, about a third (31%) both postprandial and fasting hypoglycemia, and 6.9% postprandial hypoglycemia only. Time to glucose nadir (37.3 ± 6.5 mg/dL) in the fasting test was 9.0 ± 4.4 h, with maximal insulin levels of 25.0 ± 20.3 μU/mL. Abdominal CT detected insulinoma in 75% of patients. Twenty-seven (93.1%) patients underwent surgery [enucleation, 18 (66.7%) and subtotal pancreatectomy, 9 (33.3%); tumor size, 1,7 ± 0,7 cm]. Surgery achieved cure in the majority (n = 24, 88.9%) of patients. CONCLUSION: In our setting, insulinoma is usually a benign, small, and solitary tumor, mainly affecting women aged 45-50 years, and usually localized with abdominal CT. The most commonly used surgical technique is enucleation, which achieves a high cure rate

Genetic disorders of pediatric MEN2A patients in the south of Spain

INTRODUCTION: Medullary thyroid carcinoma (MTC) is observed in nearly 100 % of patients with multiple endocrine neoplasia type 2A (MEN2A). The gene responsible for MEN2A is the RET proto-oncogene and about 95 % of MEN2A patients have germline mutations in five specific cysteine codons (609, 611, 618, 620 and 634). MATERIALS AND METHODS: A retrospective study of children from families with MEN2A in our geographic area was performed. Variables analyzed included demographic data, kinship relations, age at genetic screening, age at prophylactic thyroidectomy, genetic mutation subtype and histological findings. The genetic study consisted in direct molecular analysis by automatic sequencing of RET mutated exon in the studied family. RESULTS: We performed 13 prophylactic total thyroidectomies from 1997 to 2013, 8 females and 5 males. The mean age at genetic diagnosis was 3.8 years (range 2-5.9). All children belonged to four interconnected families living in the same geographic area and presenting C634Y mutation in all the cases. The mean age at prophylactic thyroidectomy was 5.6 years (range 4-8.5). Histopathological findings demonstrated seven cases of C-cells nodular hyperplasia, one lymphocytic thyroiditis, two without evidence of disease, two micro-carcinomas and one multicentric carcinoma. CONCLUSION: The mutation found in the RET proto-oncogene responsible for MEN2A in pediatric patients in the south of Spain is the C635Y. It is considered a high-risk mutation, associated with an earlier malignant transformation and development of MTC (AU)

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Hereditary hyperparathyroidism syndromes.

Primary hyperparathyroidism is a common endocrine disorder, resulting from a persistent hypercalcemia along with an inadequate secretion of parathyroid hormone. In approx 95% of cases, it occurs sporadically; rarely, it is part of familial syndromes. These inherited syndromes typically present at an earlier age than the nonheritable form and occur with equal frequencies in both sexes. The differential diagnosis is often difficult, but it is of fundamental importance for the management of patients and their family. The availability of specific genetic tests has improved the diagnostic accuracy allowing early diagnosis in asymptomatic family members. Before the advent of genetic testing, a definitive diagnosis could be made only in symptomatic cases based on clinical data and family history.

MENX.

Multiple endocrine neoplasias (MEN) are a group of hereditary disorders characterized by tumors arising in more than one neuroendocrine tissue. There are two major forms which can occur in humans, MEN type 1 (MEN1) and MEN type 2 (MEN2). These syndromes are transmitted as autosomal dominant traits with high penetrance and have a different tumor spectrum. MEN1 and MEN2 are caused by germline mutations in the MEN1 and RET genes, respectively. Recently, a variant of the MEN syndromes was discovered in a rat colony and was named MENX since affected animals develop tumors with a spectrum that shares features with both MEN1 and MEN2 human syndromes. Extensive genetic studies identified a germline mutation in the Cdkn1b gene, encoding the p27 cell cycle inhibitor, as the causative mutation for MENX. Capitalizing on these findings, heterozygous germline mutations in the human homologue, CDKN1B, were searched for and identified in patients with multiple endocrine tumors. As a consequence of this discovery, a novel human MEN syndrome, named MEN4, was recognized which is caused by mutations in p27. Altogether these studies identified Cdkn1b/CDKN1B as a novel tumor susceptibility gene for multiple endocrine tumors in both rats and humans. Here I review the phenotypic features and the genetics of the MENX rat syndrome. I briefly address the main functions of p27 and how they are affected by the MENX-associated mutation. Finally, I present examples of how this animal model might be exploited as a translational platform for preclinical studies of pituitary adenomas.

Medullary thyroid microcarcinoma: a population-level analysis of 310 patients.

BACKGROUND: Medullary thyroid microcarcinomas (microMTCs) are medullary thyroid carcinomas (MTCs) that measure ≤1 cm in size for which there is a paucity of data on incidence, characteristics, and clinical significance. METHODS: Patients who had a diagnosis of microMTC were abstracted from the Surveillance, Epidemiology, and End Results database (1988-2007). The data were analyzed using chi-square tests, t tests, and log-rank tests; multivariate logistic regression was used to identify factors that were associated independently with lymph node metastases. Tests for diagnostic accuracy, including likelihood ratio tests and post-test probability tests, were computed to evaluate the size-specific likelihood of developing lymph node metastases among patients with microMTC. RESULTS: In total, 310 patients had microMTC; its incidence increased during the study period (P(trend) = .033), and microMTC as a proportion of all MTCs increased by 39%. The mean tumor size was 5.7 mm. Thirty-one percent of tumors were multifocal, and 7.8% had extrathyroid extension. Lymph node metastases occurred in nearly 37% of patients who had any lymph nodes removed (65 of 176 patients). Nearly 20% of patients had regional disease, and 5% had distant metastases. The overall 10-year survival rates for patients with localized, regional, and distant disease stages were 96%, 87%, and 50%, respectively (P < .001). After adjustment, extrathyroid extension (odds ratio [OR], 41.9; P < .001) and tumor size (OR, 1.2; P = .008) retained an independent association with lymph node metastases. MTCs that measured ≤5 mm were associated with a probability of lymph node metastases of approximately 23%, and the probability increased for patients who had tumors >5 mm. CONCLUSIONS: The current results indicated that microMTCs have significant rates of poor prognostic features known to impact the survival of patients with MTC. These microcarcinomas are an important clinical entity that requires comprehensive evaluation and surgical management.

Glucagon expression in cystic pancreatic neuroendocrine neoplasms: an immunohistochemical analysis.

Pancreatic neuroendocrine neoplasms (P-NENs) are usually solid and only rarely cystic. Glucagon expression and the association with multiple endocrine neoplasia type 1 (MEN1) seem to be common in cystic P-NENs. In this study, we analyzed 404 P-NENs to gain information about the relative frequency of grossly cystic P-NENs and their association with glucagon production by the tumor cells. Three hundred forty-six solitary P-NENs and 58 P-NENs (>1 cm in diameter) from 35 patients with an MEN1 syndrome were studied. Immunostaining was performed for the four pancreatic hormones; 5.5% (19/346) of the sporadic P-NENs showed unilocular or multilocular cystic changes that were macroscopically detectable. Sixty-three percent of the solitary cystic P-NENs (versus 7% of the solitary non-cystic P-NENs) expressed predominantly glucagon. In MEN1-associated P-NENs, the relative frequency of cystic tumors was 10.3%, and all of them expressed glucagon. None of the glucagon-positive cystic P-NENs were associated with a glucagonoma syndrome. Solitary non-MEN1-associated and MEN1-associated cystic P-NENs are predominantly non-syndromic glucagon-expressing tumors. However, cystic insulinomas may also occur. Cyst formation seems to be related to hormone production.

[Clinical characteristics of multiple endocrine neoplasia]. / Séance dédiée aux tumeurs endocrines. Néoplasies endocriniennes multiples, aspects cliniques.

Multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2) are autosomal dominant inherited multiglandular diseases with familial and individual age-related penetrance and variable expression. The most frequent endocrine features of MEN1 are parathyroid involvement (> 95%), duodeno-pancreatic endocrine tissue involvement (80%), pituitary adenoma (30%), and adrenal cortex tumors (25%), with no clear syndromic variants. Identification of the germline MEN1 mutation confirms the diagnosis, but there is no phenotype-genotype correlation. All patients with MEN2 have medullary thyroid carcinoma (MTC). The most distinctive MEN2 variants are MEN2A (MTC+pheochromocytoma+hyperparathyroidism), MEN2B (MTC+pheo), and isolated familial MTC (FMTC). The prognosis of MEN2 is linked to the progression of MTC, which depends mainly on the stage at diagnosis and the quality of initial surgical treatment. This emphasizes the need for early diagnosis and management. The specific RET codon mutation correlates with the MEN2 syndromic variant and with the age of onset and aggressiveness of MTC. Consequently, RET mutational status should guide major management decisions, such as whether and when to perform thyroidectomy.

[Multiple endocrine neoplasia: genetic aspects]. / Néoplasies endocriniennes multiples, aspects génétiques.

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.

Prevalence of AIP mutations in a large series of sporadic Italian acromegalic patients and evaluation of CDKN1B status in acromegalic patients with multiple endocrine neoplasia.

BACKGROUND: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene and the p27(KIP1) encoding gene CDKN1B have been associated with two well-defined hereditary conditions, familial isolated pituitary adenoma (FIPA) and multiple endocrine neoplasia type 4 (MEN4). Somatotropinomas are present in most AIP mutated FIPA kindreds, as well as in two-thirds of MEN4 patients who carry pituitary tumors. METHODS: Germline DNA samples of 131 Italian sporadic acromegalic patients including 38 individuals with multiple tumors, and of six FIPA families (four homogeneous for prolactinomas and two heterogeneous with prolactin/nonfunctioning pituitary adenomas) were collected in a multicentric collaborative study. The prevalence of AIP and CDKN1B gene point mutations and copy number variations were evaluated. RESULTS: Two novel (IVS3+1G>A and c.871G>A) and one previously described (c.911G>A) AIP mutations were detected in four apparently sporadic cases (3.1%) with relatively high age at diagnosis (49+/-18, range 30-67). No mutations/rearrangements were detected in FIPA families. The highly conserved c.871G>A substitution was detected in a patient who also carried a MEN1 mutation suggesting that she is a double heterozygote. The possible pathogenic effect on AIP splicing of the silent substitution c.144G>A found in another patient was ruled out using a minigene-based approach. CDKN1B mutations/rearrangements were neither identified in patients with multiple neoplasia nor in FIPA families. CONCLUSION: AIP is mutated in about 3% of apparently sporadic acromegalic patients. The relatively high age at diagnosis, as well as its sporadic presentation, suggests that these patients are carriers of mutations with reduced pathogenicity. p27(KIP1) is unlikely to represent the common unifying nonendocrine etiology for acromegaly and cancer.