Total parathyroidectomy in a large cohort of cases with hyperparathyroidism associated with multiple endocrine neoplasia type 1: experience from a single academic center.

Most cases of sporadic primary hyperparathyroidism present disturbances in a single parathyroid gland and the surgery of choice is adenomectomy. Conversely, hyperparathyroidism associated with multiple endocrine neoplasia type 1 (hyperparathyroidism/multiple endocrine neoplasia type 1) is an asynchronic, asymmetrical multiglandular disease and it is surgically approached by either subtotal parathyroidectomy or total parathyroidectomy followed by parathyroid auto-implant to the forearm. In skilful hands, the efficacy of both approaches is similar and both should be complemented by prophylactic thymectomy. In a single academic center, 83 cases of hyperparathyroidism/ multiple endocrine neoplasia type 1 were operated on from 1987 to 2010 and our first surgical choice was total parathyroidectomy followed by parathyroid auto-implant to the non-dominant forearm and, since 1997, associated transcervical thymectomy to prevent thymic carcinoid. Overall, 40% of patients were given calcium replacement (mean intake 1.6 g/day) during the first months after surgery, and this fell to 28% in patients with longer follow-up. These findings indicate that several months may be needed in order to achieve a proper secretion by the parathyroid auto-implant. Hyperparathyroidism recurrence was observed in up to 15% of cases several years after the initial surgery. Thus, long-term follow-up is recommended for such cases. We conclude that, despite a tendency to subtotal parathyroidectomy worldwide, total parathyroidectomy followed by parathyroid auto-implant is a valid surgical option to treat hyperparathyroidism/multiple endocrine neoplasia type 1. Larger comparative systematic studies are needed to define the best surgical approach to hyperparathyroidism/multiple endocrine neoplasia type 1.

Total parathyroidectomy in a large cohort of cases with hyperparathyroidism associated with multiple endocrine neoplasia type 1: experience from a single academic center

Most cases of sporadic primary hyperparathyroidism present disturbances in a single parathyroid gland and the surgery of choice is adenomectomy. Conversely, hyperparathyroidism associated with multiple endocrine neoplasia type 1 (hyperparathyroidism/multiple endocrine neoplasia type 1) is an asynchronic, asymmetrical multiglandular disease and it is surgically approached by either subtotal parathyroidectomy or total parathyroidectomy followed by parathyroid auto-implant to the forearm. In skilful hands, the efficacy of both approaches is similar and both should be complemented by prophylactic thymectomy. In a single academic center, 83 cases of hyperparathyroidism/ multiple endocrine neoplasia type 1 were operated on from 1987 to 2010 and our first surgical choice was total parathyroidectomy followed by parathyroid auto-implant to the non-dominant forearm and, since 1997, associated transcervical thymectomy to prevent thymic carcinoid. Overall, 40% of patients were given calcium replacement (mean intake 1.6 g/day) during the first months after surgery, and this fell to 28% in patients with longer follow-up. These findings indicate that several months may be needed in order to achieve a proper secretion by the parathyroid auto-implant. Hyperparathyroidism recurrence was observed in up to 15% of cases several years after the initial surgery. Thus, long-term follow-up is recommended for such cases. We conclude that, despite a tendency to subtotal parathyroidectomy worldwide, total parathyroidectomy followed by parathyroid auto-implant is a valid surgical option to treat hyperparathyroidism/multiple endocrine neoplasia type 1. Larger comparative systematic studies are needed to define the best surgical approach to hyperparathyroidism/multiple endocrine neoplasia type 1.

Caracterização do fenótipo e rastreamento gênico em famílias com neoplasia endócrina múltipla tipo 2A devido à nova dupla mutação germinativa C634Y/Y791F no proto-oncogene RET / Phenotype characterization and genetic screening in multiple endocrine neoplasia type 2A families associated with the new double germline mutation C634Y/Y791F in the RET proto-oncogene

INTRODUÇÃO: A imensa maioria dos casos com Neoplasia Endócrina Múltipla Tipo 2 (NEM2) é causada por uma única mutação germinativa no proto-oncogene RET. Entretanto, há alguns poucos casos descritos na literatura (~16) que apresentam duplas mutações/polimorfismos no gene RET, geralmente associados a fenótipos atípicos. OBJETIVOS: Os objetivos deste projeto são: a) caracterizar os aspectos clínicos de pacientes advindos de cinco famílias não relacionadas com diagnóstico de NEM2A, nas quais se documentou a presença de uma nova dupla mutação germinativa RET nos códons 634 e 791 e b) realizar rastreamento gênico familiar dos casos sob-risco com a finalidade de identificarmos possíveis casos com esta nova mutação. PACIENTES: Cinco casos-índice foram recentemente descobertos albergando a dupla mutação germinativa RET C634Y/Y791F. Nestas famílias há relato de 208 parentes, potencialmente, sob-risco (~50%) de serem portadores desta mutação. Dentre estes 208 indivíduos, 81 (38,9%) aceitaram participar do rastreamento gênico. MÉTODOS: O estudo foi realizado na Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. O DNA do sangue periférico dos pacientes e de seus parentes sob- risco foi obtido após a obtenção do consentimento livre e esclarecido. Após PCR, foi realizado o sequenciamento gênico direto (ABI 3130x/l Sequencer, Applied Biosystems), abrangendo todos os 20 éxons do RET. Foram investigados potenciais polimorfismos e mutações no RET. Os tumores NEM2-relacionados (carcinoma medular de tireoide, CMT; feocromocitoma, FEO; hiperparatireoidismo primário, HPT) foram estudados quanto a vários parâmetros clínicos, como: sinais/sintomas; dimensão, penetrância e agressividade dos tumores; porcentagem de remissão bioquímica do CMT, e recidiva ou persistência dos tumores. RESULTADOS: Dentre os 81 indivíduos que participaram do rastreamento gênico, documentamos 28 casos (34,5%) como portadores da dupla mutação RET C634Y/...

INTRODUCTION: The vast majority of cases with multiple endocrine neoplasia type 2A (MEN2A) is caused by a single germline mutation in the RET proto-oncogene. However, some instances (~16) of double germline RET mutations have been reported, most frequently associated with atypical phenotypes. OBJECTIVES: The main goals of this project were: a) to characterize the phenotype of patients from five unrelated MEN2A families harboring a new RET double germline in codons 634 and 791; b) perform the genetic screening in at-risk family members attempting to search for new similarly affected cases. PATIENTS: Five affected index-cases were recently found with this new double RET mutation C634Y/Y791F. In these five families, 208 first-degree relatives were reported and they were at-risk (~50%) to develop this mutation. Eighty-one individuals out of the 208 at-risk relatives (38.9%) were available and signed the informed consent. METHODS: The present investigation was performed at the Department of Endocrinology, School of Medicine, University of São Paulo. DNA was obtained from the peripheral blood of patients and at-risk relatives, after obtaining the informed consent of all individuals. After PCR, the direct genetic sequence was performed (ABI 3130x/l Sequencer, Applied Biosystems), involving all 20 exons of the RET proto-oncogene. Potential mutations and polymorphisms were investigated. In addition, the mutations were tested in vitro and a potential founder effect was evaluated. The MEN2A- related tumors (medullary thyroid carcinoma, MTC; pheochromocytoma, PHEO; and primary hyperparathyroidism, HPT) were approached using several clinical parameters, as: signs and symptoms; age at the diagnosis; tumor size and aggressiveness; biochemical remission of MTC; tumor relapse or persistence; RESULTS: Within the 81 genetically screened individuals, 28 cases (34.5%) were documented harboring the RET C634Y/Y791F germline mutation. It was observed that: a) the five affected...

The impact of clinical and genetic screenings on the management of the multiple endocrine neoplasia type 1.

PURPOSE: To perform clinical and genetic screening for multiple endocrine neoplasia type 1 (MEN1) in patients at the Academic Hospital of the University of São Paulo School of Medicine, and to analyze its impact on clinical management of patients with MEN1. METHODS: The clinical diagnosis of MEN1 was made in accordance with the Consensus on multiple endocrine neoplasias. Mutation analysis of the entire MEN1 tumor suppressor gene and genetic screening of at-risk family members were performed by direct sequencing. To analyze the implementation of genetic diagnosis, the studied patients were separated into 3 groups: MEN1 index cases (group I), clinically diagnosed MEN1 cases (group II), and genetically diagnosed MEN1 cases (group III). RESULTS: In total, 154 individuals were clinically and genetically studied. We identified 12 different MEN1 mutations. Fifty-two MEN1 cases were identified: 13 in group I, 28 in group II, and 11 in group III. The mean age in group III (27.0 years) was significantly lower than in groups I (39.5 years) and II (42.4 years; P = 0.03 and P = 0.01, respectively). Patients in groups I and II mostly presented 2 or 3 MEN1-related tumors, while 81.8% of those in group III presented 1 or no MEN1-related tumor. Additionally, in group III, 45.4% of cases were asymptomatic, and no metastasis or death was verified. Surveillance for MEN1 mutations allowed the exclusion of 102 noncarriers, including a case of MEN1 phenocopy. CONCLUSION: Our data supports the benefits of clinical and genetic screening for multiple endocrine neoplasia type 1 in the management of this syndrome.

The impact of clinical and genetic screenings on the management of the multiple endocrine neoplasia type 1

PURPOSE: To perform clinical and genetic screening for multiple endocrine neoplasia type 1 (MEN1) in patients at the Academic Hospital of the University of São Paulo School of Medicine, and to analyze its impact on clinical management of patients with MEN1. METHODS: The clinical diagnosis of MEN1 was made in accordance with the Consensus on multiple endocrine neoplasias. Mutation analysis of the entire MEN1 tumor suppressor gene and genetic screening of at-risk family members were performed by direct sequencing. To analyze the implementation of genetic diagnosis, the studied patients were separated into 3 groups: MEN1 index cases (group I), clinically diagnosed MEN1 cases (group II), and genetically diagnosed MEN1 cases (group III). RESULTS: In total, 154 individuals were clinically and genetically studied. We identified 12 different MEN1 mutations. Fifty-two MEN1 cases were identified: 13 in group I, 28 in group II, and 11 in group III. The mean age in group III (27.0 years) was significantly lower than in groups I (39.5 years) and II (42.4 years; P = 0.03 and P = 0.01, respectively). Patients in groups I and II mostly presented 2 or 3 MEN1-related tumors, while 81.8 percent of those in group III presented 1 or no MEN1-related tumor. Additionally, in group III, 45.4 percent of cases were asymptomatic, and no metastasis or death was verified. Surveillance for MEN1 mutations allowed the exclusion of 102 noncarriers, including a case of MEN1 phenocopy. CONCLUSION: Our data supports the benefits of clinical and genetic screening for multiple endocrine neoplasia type 1 in the management of this syndrome.

OBJETIVOS: Realizar rastreamentos clínico e gênico para Neoplasia Endócrina Múltipla tipo 1 (NEM1) e analisar seu impacto no seguimento clínico desses pacientes no Hospital das Clínicas, SP. MÉTODOS: O diagnóstico clínico de NEM1 foi realizado de acordo com o Consenso sobre neoplasias endócrinas múltiplas. A análise genética para identificação de mutações foi realizada por sequenciamento automático de todas as regiões codificadoras e fronteiras exon/intron do gene MEN1. Os casos afetados foram sub-divididos em 3 grupos e analisados separadamente: casos-índices (grupo I), familiares diagnosticados clinicamente (grupo II) e genicamente (grupo III). RESULTADOS: Um total de 154 casos participou desse estudo, sendo 52 diagnosticados com NEM1: 13 do grupo I, 28 do grupo II e 11 do grupo III. A idade média ao diagnóstico no grupo III (27 anos) foi significativamente menor que a dos grupos I (39,5 anos; p = 0,03) e II (42,4 anos; p = 0,01). A maioria dos pacientes dos grupos I e II apresentou 2 ou 3 tumores, enquanto que 81,8 por cento dos casos do grupo III apresentavam 1 ou nenhum tumor relacionado à NEM1. Além disto, 45,4 por cento dos casos do grupo III eram assintomáticos, não sendo observados nenhuma metástase ou óbito. Os demais 102 familiares sob-risco estudados não herdaram mutação MEN1 e foram excluídos do rastreamento clínico. Um caso de fenocópia NEM1 foi também localizado. DISCUSSÃO: Nossos dados demonstraram importantes benefícios no seguimento dos pacientes NEM1, obtidos pela implementação dos rastreamentos clínico e gênico para essa doença.