Case report: Comprehensive follow-up of a Colombian family carrying a novel MEN1 variant linked to a rare ACTH-producing pancreatic neuroendocrine carcinoma.

Background: Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disorder marked by pathogenic variants in the MEN1 tumor suppressor gene, leading to tumors in the parathyroid glands, pancreas, and pituitary. The occurrence of ACTH-producing pancreatic neuroendocrine carcinoma is exceedingly rare in MEN1. Case presentation: This report details a Colombian family harboring a novel MEN1 variant identified through genetic screening initiated by the index case. Affected family members exhibited primary hyperparathyroidism (PHPT) symptoms from their 20s to 50s. Uniquely, the index case developed an ACTH-secreting pancreatic neuroendocrine carcinoma, a rarity in MEN1 syndromes. Proactive screening enabled the early detection of pituitary neuroendocrine tumors (PitNETs) as microadenomas in two carriers, with subsequent surgical or pharmacological intervention based on the clinical presentation. Conclusion: Our findings underscore the significance of cascade screening in facilitating the early diagnosis and individualized treatment of MEN1, contributing to better patient outcomes. Additionally, this study brings to light a novel presentation of ACTH-producing pancreatic neuroendocrine carcinoma within the MEN1 spectrum, expanding our understanding of the disease's manifestations.

Neoplasia endócrina múltiple y enfermedad inflamatoria intestinal de inicio muy temprano. Una asociación inesperada / Multiple endocrine neoplasia and very early onset in flammatory bowel disease. An unexpected association

Resumen La enfermedad inflamatoria intestinal de inicio muy temprano (VEOIBD) es una entidad rara en pediatría. Es conocida su asociación con inmunodeficiencias prima rias de origen monogénico. Presentamos el caso de una paciente con diagnóstico de VEOIBD a quien se le realizó una secuenciación masiva del exoma. El resultado del estudio permitió identificar una variante patogénica en el proto oncogen RET, asociada con enfermedad neoplasia endocrina múltiple tipo 2A. No hay reportes de asociación de variantes en el proto oncogen RET con VEOIBD. No se puede adjudicar la presencia de estas dos entidades clínicas a una única causa genética.

Abstract Very early onset inflammatory bowel disease (VEOI BD) is a rare entity in pediatrics. Its association with pri mary immunodeficiencies of monogenic origin is known. We present the case of a patient diagnosed with VEOIBD who underwent massive paralleled exome sequencing. The result of the study showed a pathogenic variant in the RET proto-oncogene, associated with multiple endo crine neoplasia type 2A disease. There are no previous reports of association of RET proto-oncogene variants with VEOIBD. The presence of these two clinical entities cannot be attributed to a single genetic cause.

Phenotype and genotype of patients with multiple endocrine neoplasia type 1 studied in Argentina.

INTRODUCTION: Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant inherited disease with an estimated prevalence of 2-10:100 000. The main locations of tumors are parathyroid glands (HPT), gastroenteropancreatic tract (GEPT), and anterior pituitary gland (PT). The aim of our investigation was to describe the phenotype and genotype of Argentinian patients with MEN1. METHODS: A total of 68 index patients diagnosed with at least two of the three main tumors or one tumor and a relative with MEN1, and 84 first-degree relatives were studied. We sequenced the coding region (exons 2-10); the promoter, exon 1; and the flanking intronic regions of the MEN1 gene, following the Sanger method. We used MLPA in index patients without mutation. RESULTS: Prevalence of tumors: HPT 87.5%, GEPT 49% (p< 0.001). No statistical differences in the prevalence of HPT vs. PT (68%). Prevalence of pathogenic variants: 90% in familial cases and 51% in sporadic cases. Of the different 36 pathogenic variants, 13 (36.2%) were frameshift micro-rearrangement, 8 (22.2%) were missense, 9 (25%) were nonsense, 3 (8.3%) were mutations in splicing sites, 2 (5.5%) were large deletions and, 1 in-frame micro-rearrangement. We found 7 novel pathogenic variants. Thirty-nine percent (n = 33) of first-degree relatives of 23 families were found to be mutation carriers. CONCLUSION: The phenotype and genotype of Argentinian patients was similar to other MEN1 populations. A high frequency of PT and the identification of seven novel mutations are underscored.

Introducción: La neoplasia endocrina múltiple tipo 1 (NEM1) es una enfermedad hereditaria autosómica dominante con una prevalencia estimada de 2-10:100 000. Las localizaciones principales de los tumores son glándulas paratiroides (HPT), tracto gastroenteropancreático (TGEP) y glándula pituitaria (TP). El objetivo de nuestra investigación fue describir el fenotipo y genotipo de pacientes argentinos con NEM1. Métodos: Estudiamos 68 casos índices diagnosticados por presentar al menos dos de los tres tumores principales, o un tumor y un pariente con NEM1, y 84 familiares de primer grado. Secuenciamos la región codificante (exones 2-10); el promotor, exón 1; y las regiones intrónicas flanqueantes del gen MEN1 siguiendo el método de Sanger. Utilizamos MLPA en pacientes índice sin mutación. Resultados: Prevalencia de tumores: HPT 87.5%, TGEP 49% (p < 0.001), sin diferencias estadísticas entre las prevalencias de HPT vs TP (68%). Prevalencia de variantes patogénicas: 90% en casos familiares y 51% en esporádicos. Hallamos 36 variantes patogénicas, 7 (20%) fueron noveles. Fueron 13 (36.2%) microarreglos con cambio en el marco de lectura, 9 (25%) variantes sin sentido, 8 (22.2%) con cambio de sentido, 3 (8.3%) en sitio de unión de empalme, 2 (5.5%) grandes deleciones y 1 microarreglo sin cambio en el marco de lectura. El 39 % (n = 33) de los parientes de primer grado en 23 familias fueron portadores de mutaciones. Conclusión: El fenotipo y genotipo de los pacientes argentinos con NEM1 fue similar al de otras poblaciones. Destacamos una alta frecuencia de TP y de variaciones patogénicas noveles.

[Multiple endocrine neoplasia and very early onset inflammatory bowel disease. An unexpected association]. / Neoplasia endócrina múltiple y enfermedad inflamatoria intestinal de inicio muy temprano. Una asociación inesperada.

Very early onset inflammatory bowel disease (VEOIBD) is a rare entity in pediatrics. Its association with primary immunodeficiencies of monogenic origin is known. We present the case of a patient diagnosed with VEOIBD who underwent massive paralleled exome sequencing. The result of the study showed a pathogenic variant in the RET proto-oncogene, associated with multiple endocrine neoplasia type 2A disease. There are no previous reports of association of RET proto-oncogene variants with VEOIBD. The presence of these two clinical entities cannot be attributed to a single genetic cause.

La enfermedad inflamatoria intestinal de inicio muy temprano (VEOIBD) es una entidad rara en pediatría. Es conocida su asociación con inmunodeficiencias primarias de origen monogénico. Presentamos el caso de una paciente con diagnóstico de VEOIBD a quien se le realizó una secuenciación masiva del exoma. El resultado del estudio permitió identificar una variante patogénica en el proto oncogen RET, asociada con enfermedad neoplasia endocrina múltiple tipo 2A. No hay reportes de asociación de variantes en el proto oncogen RET con VEOIBD. No se puede adjudicar la presencia de estas dos entidades clínicas a una única causa genética.

RET 634 germline/gonadal mosaicism generating a second pathogenic amino acid change in multiple endocrine neoplasia type 2A.

Genetic testing for germline RET pathogenic variants, which cause the Multiple Endocrine Neoplasia Type 2 (MEN2) syndrome, has become crucial in managing patients with medullary thyroid carcinoma (MTC). Classically, RET heterozygous missense pathogenic variants are transmitted in a Mendelian autosomal dominant pattern, of which germline/gonadal mosaicism has never been reported. We report the novel occurrence of a MEN2A patient's family in which the siblings inherited three different RET 634 genotypes: wild type (p.Cys634), p.Cys634Gly or p.Cys634Arg heterozygous pathogenic variants. We hypothesized that germline/gonadal mosaicism, derived from an inherited + early somatic mutation in the mother or a double de novo mutation during maternal embryogenesis, led to this rare event in the RET gene. Exome analysis of the proband's deceased mother's paraffin-embedded thyroid tissue confirmed the three nucleotides in the same 634 codon position. For the first time, we describe germline/gonadal mosaicism in RET, generating a second pathogenic amino acid change in the same codon causing MEN2A. Our finding shows that RET parental mosaicism, confirmed by somatic exome sequencing, might explain discrepant genotype cases in siblings with inherited cancers.

Neoplasia endocrina múltiple tipo 1 en paciente con diagnóstico de nesidioblastosis. Presentación de un caso

Las neoplasias endocrinas múltiples engloban una serie de síndromes caracterizados por su origen genético y la afectación de una o más glándulas. Se describe el caso de un paciente masculino, de 23 años, con antecedentes de salud de nesidioblastosis diagnosticado a los 16 años de edad, quien acudió al Hospital General Docente Ambato por presentar convulsiones tónico clónicas, e hipoglucemia severa con posterior estatus epiléptico. Los estudios de laboratorio mostraron hiperparatiroidismo primario, y los de imagen identificaron lesiones sugerentes de adenoma paratiroideo e insulinoma de cabeza de páncreas. Después de analizar el caso, se identificaron dos criterios para plantear una neoplasia endocrina múltiple tipo 1: presencia de insulinoma e hiperparatiroidismo primario. Además de tratamiento con bifosfonato, se planificó interconsulta con el servicio de Genética, para estudio del paciente y familiares; y con Cirugía General, para programación de resolución quirúrgica. Debido a la poca frecuencia de esta enfermedad, resulta de interés describir el caso, con el objetivo de exponer las principales manifestaciones clínicas y conducta a seguir. Constituye una prioridad el diagnóstico de su causa en cada paciente.

Multiple endocrine neoplasias encompass a series of syndromes characterized by their genetic origin and the involvement of one or more glands. A 23-years-old male patient with a health history of nesidioblastosis diagnosed at 16 years of age, who attended the Ambato General Teaching Hospital with tonic-clonic seizures and severe hypoglycemia with subsequent epileptic status, is described. Laboratory studies showed primary hyperparathyroidism, and imaging identified lesions suggestive of parathyroid adenoma and insulinoma of the head of the pancreas. After analyzing the case, two criteria were identified to suggest multiple endocrine neoplasia type 1: presence of insulinoma and primary hyperparathyroidism. In addition to treatment with bisphosphonate, consultation with the Genetics service was planned for study of the patient and family members; and with General Surgery, for scheduling surgical resolution. Due to the infrequency of this disease, it is of interest to describe the case, with the aim of exposing the main clinical manifestations and conduct to follow. Diagnosing its cause in each patient is a priority.

Clinical and molecular features of four Brazilian families with multiple endocrine neoplasia type 1.

Objective: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized by its clinical variability and complexity in diagnosis and treatment. We performed both clinical and molecular descriptions of four families with MEN1 in a follow-up at a tertiary center in Brasília. Methods: From a preliminary review of approximately 500 medical records of patients with pituitary neuroendocrine tumor (PitNET) from the database of the Neuroendocrinology Outpatient Clinic of the University Hospital of Brasília, a total of 135 patients met the criteria of at least two affected family members. From this cohort, we have identified 34 families: only four with a phenotype of MEN1 and the other 30 families with the phenotype of familial isolated pituitary adenoma (FIPA). Eleven patients with a clinical diagnosis of MEN1 from these four families were selected. Results: Variants in MEN1 gene were identified in all families. One individual from each family underwent genetic testing using targeted high-throughput sequencing (HTS). All patients had primary hyperparathyroidism (PHPT), and the second most common manifestation was PitNET. One individual had well-differentiated liposarcoma, which has been previously reported in a single case of MEN1. Three variants previously described in the database and a novel variant in exon 2 have been found. Conclusions: The study allowed the genotypic and phenotypic characterization of families with MEN1 in a follow-up at a tertiary center in Brasília.

RET gene mutational diagnosis and precision medicine in Mexico.

Precision medicine is a reality in some diseases; it supports the development of accurate and specific diagnostic methods, new drugs and molecules. Our research team in Mexico, made up of clinical and biomedical researchers, has been performing free RET gene mutational diagnosis for medullary thyroid cancer and multiple endocrine neoplasia (MEN) 2 and 3 for 20 years. RET pathogenic variants in the Mexican population are consistent with reported data: most common mutations are 634/NEM2 and 918/NEM3. Currently, new nanobiotechnology methods are being developed for this type of determination in order to obtain faster, simpler, more sensitive and specific results applicable in all types of laboratories.

La medicina de precisión en algunas enfermedades es una realidad; respalda el desarrollo de métodos diagnósticos certeros y específicos, de nuevas drogas y moléculas. Nuestro equipo de investigación en México, conformado por investigadores clínicos y biomédicos, desde hace 20 años realiza de forma gratuita el diagnóstico mutacional del gen RET y su relación con el cáncer medular de tiroides y la neoplasia endocrina múltiple (NEM) 2 y 3. Las variantes patogénicas de RET en la población mexicana coinciden con los datos reportados: la mayoría con 634/NEM2 y 918/NEM3. Actualmente se están desarrollando nuevos métodos de nanobiotecnología para este tipo de determinaciones, de tal forma que puedan obtenerse resultados más rápidos, simples, sensibles y específicos aplicables en todo tipo de laboratorio.

Diagnóstico mutacional del gen RET y la medicina de precisión en México / RET gene mutational diagnosis and precision medicine in Mexico

Resumen La medicina de precisión en algunas enfermedades es una realidad; respalda el desarrollo de métodos diagnósticos certeros y específicos, de nuevas drogas y moléculas. Nuestro equipo de investigación en México, conformado por investigadores clínicos y biomédicos, desde hace 20 años realiza de forma gratuita el diagnóstico mutacional del gen RET y su relación con el cáncer medular de tiroides y la neoplasia endocrina múltiple (NEM) 2 y 3. Las variantes patogénicas de RET en la población mexicana coinciden con los datos reportados: la mayoría con 634/NEM2 y 918/NEM3. Actualmente se están desarrollando nuevos métodos de nanobiotecnología para este tipo de determinaciones, de tal forma que puedan obtenerse resultados más rápidos, simples, sensibles y específicos aplicables en todo tipo de laboratorio.

Abstract Precision medicine is a reality in some diseases; it supports the development of accurate and specific diagnostic methods, new drugs and molecules. Our research team in Mexico, made up of clinical and biomedical researchers, has been performing free RET gene mutational diagnosis for medullary thyroid cancer and multiple endocrine neoplasia (MEN) 2 and 3 for 20 years. RET pathogenic variants in the Mexican population are consistent with reported data: most common mutations are 634/NEM2 and 918/NEM3. Currently, new nanobiotechnology methods are being developed for this type of determination in order to obtain faster, simpler, more sensitive and specific results applicable in all types of laboratories.

Impact of parathyroidectomy on quality of life in multiple endocrine neoplasia type 1.

Background: Potential influences of parathyroidectomy (PTx) on the quality of life (QoL) in multiple endocrine neoplasia type 1-related primary hyperparathyroidism (HPT/MEN1) are unknown. Method: Short Form 36 Health Survey Questionnaire was prospectively applied to 30 HPT/MEN1 patients submitted to PTx (20, subtotal; 10, total with autograft) before, 6 and 12 months after surgery. Parameters that were analyzed included QoL, age, HPT-related symptoms, general pain, comorbidities, biochemical/hormonal response, PTx type and parathyroid volume. Results: Asymptomatic patients were younger (30 vs 38 years; P = 0.04) and presented higher QoL scores than symptomatic ones: Physical Component Summary score (PCS) 92.5 vs 61.2, P = 0.0051; Mental Component Summary score (MCS) 82.0 vs 56.0, P = 0.04. In both groups, QoL remained stable 1 year after PTx, independently of the number of comorbidities. Preoperative general pain was negatively correlated with PCS (r = -0.60, P = 0.0004) and MCS (r = -0.57, P = 0.0009). Also, moderate/intense pain was progressively (6/12 months) more frequent in cases developing hypoparathyroidism. The PTx type and hypoparathyroidism did not affect the QoL at 12 months although remnant parathyroid tissue volume did have a positive correlation (P = 0.0490; r = 0.3625) to PCS 12 months after surgery. Patients with one to two comorbidities had as pre-PTx PCS (P = 0.0015) as 12 months and post-PTx PCS (P = 0.0031) and MCS (P = 0.0365) better than patients with three to four comorbidities. Conclusion: A variable QoL profile was underscored in HPT/MEN1 reflecting multiple factors associated with this complex disorder as comorbidities, advanced age at PTx and presence of preoperative symptoms or of general pain perception. Our data encourage the early indication of PTx in HPT/MEN1 by providing known metabolic benefits to target organs and avoiding potential negative impact on QoL.

Surgical Remission of Diabetes in a Patient With Mutation of RET Proto-Oncogene.

OBJECTIVE: In pheochromocytomas, accelerated catecholamine production can cause secondary diabetes. The gene responsible for multiple endocrine neoplasia type 2 (MEN2)-related pheochromocytomas is the RET proto-oncogene. The objective of this report is to describe a unique case of surgical remission of misdiagnosed type 2 diabetes mellitus (T2DM) in a woman with bilateral pheochromocytoma and RET proto-oncogene mutation. METHODS: Clinical examination, urinary metanephrine level, triple-phase abdominal computed tomography (CT) with adrenal protocol, positron emission tomography with 18F-fluorodeoxyglucose integrated with CT, surgical pathology, and genetic testing were performed. RESULTS: A 46-year-old woman with a 5-year history of apparent T2DM complicated by neuropathy, without a contributory family history, presented with occasional headaches, weight loss, and abdominal pain. A 24-hour urinary metanephrine of 5 mg (reference range, 0.05-1 mg) was found. Abdominal CT showed bilateral adrenal masses with <60% washout. Positron emission tomography with 18F-fluorodeoxyglucose integrated with CT showed a left solid-cystic lesion with low metabolic activity and a right nodular lesion with a higher metabolic activity, which was conclusive of bilateral pheochromocytoma. The remission of diabetes was achieved 1 year after a bilateral adrenalectomy. In addition, a multinodular goiter was found, and a fine-needle aspiration biopsy confirmed that it was a medullary thyroid carcinoma. A heterozygous pathogenic variant of the RET proto-oncogene was found and MEN2A was confirmed. CONCLUSION: This is the first report of a patient with a RET proto-oncogene mutation experiencing remission of diabetes after surgical resection of bilateral pheochromocytomas. Timely recognition and treatment of the underlying condition are important to potentially achieve diabetes remission and prevent its long-term complications.

Neoplasia endocrina múltiple IIA: feocromocitoma bilateral. A propósito de un caso y revisión de la literatura / Multiple Endocrine Neoplasia IIA: Bilateral Pheochromocytoma. About a Case and Literature Review

Resumen: Presentamos el caso de una paciente del sexo femenino, de 54 años de edad, con antecedente familiar de neoplasia endocrina múltiple tipo II, con estudio genético positivo para NEM 2 IIA EXON 11, c634 CGCIB. Inició padecimiento con cardiopatía hipertensiva y disfunción diastólica, hallazgo to mográfico de tumor suprarrenal bilateral por imagenología, se realizó adrenalectomía convencional transabdominal, se encontró tumor derecho con cápsula correspondiente a feo cromocitoma con un peso de 1,100 g de 14.5 cm de diámetro mayor con invasión a cápsula sin romperla, tumor suprarrenal izquierdo correspondiente a feocromocitoma con un peso de 950 g de 15 cm de diámetro mayor.

Abstract: We present the case of a 54-year-old female patient with a family history of multiple endocrine neoplasia type II, with a genetic study for MEN 2 IIA EXON 11, CG6B c634, onset with hypertensive heart disease and diastolic dysfunction, tomographic finding of bilateral adrenal tumor by imaging. A conventional transabdominal adrenalectomy was performed, finding a right tumor with a capsule corresponding to pheochromocytoma with a weight of 1,100 g of 14.5 cm of greater diameter with invasion of the capsule without breaking it, and a left adrenal tumor corresponding to pheochromocytoma with a weight of 950 g of 15 cm of greater diameter.

Solitary circumscribed neuroma of the conjunctiva: Differential diagnosis from neurofibroma is a must? / Neuroma circunscrito solitário da conjuntiva: diagnóstico diferencial de neurofibroma obrigatório?

ABSTRACT A 42-year-old male presented with a 4-week history of a mass in the right inferior palpebral conjunctiva close to the punctum. An excisional biopsy of the lesion and histopathological examination revealed that the mass was composed of Schwann cells with thin conical nuclei, fine chromatin, and unnoticeable nucleoli. Immunohistochemically, the spindle cells were diffusely and strongly positive for S100 protein. Neurofilament immunostaining was also positive, which highlighted axons. In light of these findings, the tumor was diagnosed as solitary circumscribed neuroma. A comprehensive evaluation for multiple endocrine neoplasia type 2b was performed. However, no multiple endocrine neoplasia type 2b stigmata and no family history were detected. The diagnosis was therefore finalized as solitary circumscribed neuroma, which is considered as a rare condition. The differential diagnosis is based on the histopathological examination and immunohistochemical evaluation. As the tumor can be related with multiple endocrine neoplasia type 2b, it is essential to systematically investigate for multiple endocrine neoplasia type 2b in such cases.

RESUMO Um homem de 42 anos apresentou uma massa na conjuntiva palpebral inferior direita, próxima ao punctum, com evolução de 4 semanas. Uma biópsia excisional da lesão e o subsequente exame anatomopatológico revelaram que a massa era composta de células de Schwann com núcleos cônicos, croma­tina fina e nucléolos não visíveis. Ao exame imuno-histoquímico, as células fusiformes mostraram-se difusa e fortemente positivas para a proteína S100. A imunocoloração também foi positiva para neurofilamentos e evidenciou os axônios. Considerando esses achados, o tumor foi diagnosticado como um neuroma circunscrito solitário. Procedeu-se uma investigação completa para neoplasia endócrina múltipla tipo 2b, entretanto, estigmas característicos e história familiar não foram detectados. Assim, o diagnóstico foi firmado como neuroma circunscrito solitário, condição rara cujo diagnóstico diferencial baseia-se no exame anatomopatológico e na avaliação imuno-histoquímica. Já que esse tumor pode estar relacionado à neoplasia endócrina múltipla tipo 2b, torna-se essencial, nesses casos, a investigação da neoplasia de forma sistemática.

Multiple endocrine neoplasia type 1 in patients with gastroenteropancreatic neuroendocrine tumors: An opportunity for early diagnosis and appropriate management.

Gastroenteropancreatic neuroendocrine tumors (GEPNET) are rare tumors that may be sporadic or develop as part of multiple endocrine neoplasia type 1 syndrome (MEN1). The aim of the present study was to report the experience of a Brazilian multidisciplinary outpatient neuroendocrine tumor clinic regarding the clinical diagnosis of MEN1 in a cohort of GEPNET patients. Patient data, including clinical characteristics and the lag time from the onset of symptoms to diagnosis of the first tumor, and further lag time until the diagnosis of MEN1, were retrospectively reviewed. Among 44 GEPNET patients, 6 had a clinical diagnosis of MEN1. Primary hyperparathyroidism and GEPNET were present in all patients in the cohort, and pituitary neuroendocrine tumors were present in 33.3%. The median time interval from the onset of initial symptoms to the diagnosis of the first tumor was 42 months (range, 0-204 months). The median time interval between the diagnosis of the first tumor and the diagnosis of MEN1 was 22 months (range, 1-109 months). The prolonged lag time between the onset of initial symptoms and MEN1 diagnosis may result in substantial morbidity and loss of opportune interventions for the patients. Therefore, greater efforts should be made to shorten these times and improve the care of patients with MEN1.

HEREDITARY PITUITARY TUMOR SYNDROMES: GENETIC AND CLINICAL ASPECTS.

The pituitary gland is responsible for the synthesis and secretion of various hormones that play a key role in regulating endocrine function and homeostasis. Pituitary adenomas (PA) are benign epithelial tumors arising from the endocrine cells of the anterior pituitary gland. Clinically relevant PA are relatively common and they occur in 0.1% of the general population. They are mostly benign monoclonal neoplasms that arise from any of the five hormone-secreting cell types of the anterior pituitary gland. PA are categorized as either functioning or non-functioning, depending on whether or not they produce a hormonal hypersecretion syndrome. Both functioning and non-functioning adenomas can produce symptoms or signs resulting from compression of the optic chiasm or invasion of cavernous sinuses. Only 5% of PA occur within the context of hereditary syndromes with reasonably well-defined oncogenic mechanisms. The vast majority of PA are sporadic, and their etiopathogenesis remains largely unknown. Pituitary tumor oncogenesis involves several mechanisms that eventually lead to abnormal cell proliferation and dysregulated hormone production. Among these factors, we found inactivating mutations of tumor suppressor genes, activating mutation of oncogenes and the participation of hormonal signals coming from the hypothalamus, all resulting in cell-cycle regulation abnormalities. In this review, we summarize the clinical and pathophysiological aspects of the different hereditary pituitary tumor syndromes.

Hereditary pituitary tumor syndromes: genetic and clinical aspects

ABSTRACT The pituitary gland is responsible for the synthesis and secretion of various hormones that play a key role in regulating endocrine function and homeostasis. Pituitary adenomas (PA) are benign epithelial tumors arising from the endocrine cells of the anterior pituitary gland. Clinically relevant PA are relatively common and they occur in 0.1% of the general population. They are mostly benign monoclonal neoplasms that arise from any of the five hormone-secreting cell types of the anterior pituitary gland. PA are categorized as either functioning or non-functioning, depending on whether or not they produce a hormonal hypersecretion syndrome. Both functioning and non-functioning adenomas can produce symptoms or signs resulting from compression of the optic chiasm or invasion of cavernous sinuses. Only 5% of PA occur within the context of hereditary syndromes with reasonably well-defined oncogenic mechanisms. The vast majority of PA are sporadic, and their etiopathogenesis remains largely unknown. Pituitary tumor oncogenesis involves several mechanisms that eventually lead to abnormal cell proliferation and dysregulated hormone production. Among these factors, we found inactivating mutations of tumor suppressor genes, activating mutation of oncogenes and the participation of hormonal signals coming from the hypothalamus, all resulting in cell-cycle regulation abnormalities. In this review, we summarize the clinical and pathophysiological aspects of the different hereditary pituitary tumor syndromes.

From 'Me' to 'Us': solidarity and biocitizenship in the Brazilian cancer precision medicine innovation system / De 'Mim' para 'Nós': solidariedade e biocidadania no sistema brasileiro de inovação em medicina de precisão para o câncer

ABSTRACT As biotechnology innovations move from the bench to the bedside and, recently, also to the Internet, a myriad of emanating challenges and potentials may rise under distinct sociocultural and political economic contexts. Using a grounded-theory-inspired case study focused on the Brazilian research consortium for Medullary Endocrine Neoplasia type 2 (BrasMEN) - an inherited syndrome where genetic tests define cost-effective interventions - we outline facilitators and barriers to both development and implementation of a 'public health genomics' strategy under a developing country scenario. The study is based on participant observation at three centres and interviews with all who might hold an interest in MEN2 around Brazil. We discuss how a 'solidarity'-based motivation for individual and collective 'biocitizenship' is driving people's pre-emptive actions for accessing and making personalised healthcare available at Brazil's Unified Health System (SUS) via the 'co-production' of science, technology and the culture for precision medicine - termed Brazil's 'hidden' biomedical innovation system. Given the establishment of BrasMEN as 'solidarity networks' - promoting and supporting the cancer precision medicine's rationale - our data illustrates how a series of new bioethical challenges raise from such engagement with familial cancer genomics under Brazil's developing country scenario and how this social/soft technology constitute a solution for Euro/North American societies.

RESUMO Ao passo em que as inovações biotecnológicas migram da bancada para o leito e, mais recentemente, também para a Internet, uma miríade de desafios e potenciais pode surgir em contextos socioculturais e político-econômicos distintos. Usando um estudo de caso inspirado na teoria embasada em dados focado no consórcio de pesquisa brasileiro sobre a Neoplasia Endócrina Múltipla do Tipo 2 (BrasMEN) - uma síndrome rara em que testes genéticos definem intervenções custo-efetivas - ressaltamos facilitadores e barreiras para ambos desenvolvimento e implementação de uma estratégia de genômica em saúde pública no cenário de um país em desenvolvimento. O estudo foi baseado em observação participante em três centros e entrevistas com todos que podem ter um interesse sobre a MEN2 no Brasil. Discutimos como uma motivação baseada em 'solidariedade' para uma 'biocidadania' individual e coletiva está impulsionando ações preventivas nas pessoas para acessar e fazer com que cuidados em saúde personalizados sejam disponibilizados no Sistema Único de Saúde (SUS) do Brasil via a 'coprodução' de ciência, tecnologia e a cultura para medicina de precisão - denominado sistema de inovação biomédico brasileiro 'escondido'. Dado o estabelecimento do BrasMEN como 'redes de solidariedade' - promovendo e apoiando a abordagem da medicina de precisão em câncer - nossos dados ilustram como uma série de novos desafios bioéticos surgem desse engajamento com a genômica do câncer familiar no cenário de país em desenvolvimento brasileiro e como esta tecnologia social/leve constitui uma solução para sociedades europeias e norte-americanas.

Laparoscopically excised retroperitoneal presacral Schwannoma: atypical pre and postoperative manifestations - case report.

BACKGROUND: We are a reporting a rare case of retroperitoneal schwanomma with atypical pre and postoperative manifestations. Retroperitoneal schwannomas are rare tumors that are difficult to preoperatively diagnose. CASE PRESENTATION: This is a case report of a male patient, 41 years old, with symptoms of hipogastric and lower right member pain, as well as a history of a papilliferous thyroid tumor. Computerized tomography exams were inconclusive, showing a mass in the presacral region with dimensions of 4.4 × 3.9 × 3.4 cm. Removal was carried out by laparoscopic surgery, with self-limited postoperative complications. Diagnosis was carried out by anatomopathological examination, and syndromic hypotheses were discarded. CONCLUSIONS: The postoperative complications of schwanomma are little reported in the literature. In the simultaneous occurrence of schwanomma and other endocrine tumors, further studies are warranted to better differentiate the cases that need investigation of syndromic causes.

Outcome and long-term follow-up of adrenal lesions in multiple endocrine neoplasia type 1

ABSTRACT Objective To describe the prevalence, clinical characteristics and outcome of adrenal lesions in long-term follow-up of Multiple endocrine neoplasia type 1 (MEN1) patients. Subjects and methods We retrospectively studied sixteen patients from six families of individuals with MEN1. Adrenal involvement was evaluated using clinical, biochemical and imaging data. Results Adrenal lesions were identified in nine of sixteen (56.3%) patients: seven women and two men (mean age: 52.2 years). Adrenal involvement was detected at MEN1 diagnosis in more than half of the patients. Eighteen adrenal nodules were founded (median of two nodules per patient) with mean adrenal lesion diameter of 17.4 mm. Three patients had unilateral adrenal involvement. Hormonal hypersecretion (autonomous cortisol secretion) was found in two patients. None of the patients was submitted to adrenalectomy, presented an aldosterone-secreting lesion, a pheochromocytoma, an adrenal carcinoma or metastatic disease during the follow-up. A predominance of stable adrenal disease, in terms of size and hormonal secretion, was observed. Adrenal lesions were evenly distributed between the germline mutations. Conclusion Adrenal tumours are a common feature of MEN1 that can affect more than half of the patients. Most of the tumours are bilateral non-functional lesions, but hormonal secretion may occur and should be promptly identified to reduce the morbidity/mortality of the syndrome. Periodic surveillance of these patients should be performed.