Neoplasia Endócrina Múltipla

Descrição Geral

Definição

As síndromes de neoplasia endócrina múltipla (MEN) são doenças genéticas caracterizadas pela presença de ≥ 2 tumores endócrinos.

Tipos

• MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia:
  • Caracterizado por um dos seguintes quadros clínicos:
    • Predileção pela hiperplasia / tumores envolvendo frequentemente as glândulas paratiroides, hipófise anterior e células das ilhotas pancreáticas
    • Presença de um tumor Tumor Inflammation associado a MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia numa família com MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia clinicamente confirmado
• MEN2:
  • Caracterizado por uma predisposição para desenvolver carcinoma medular da tiroide (CMT), tumores da paratiroide e feocromocitoma
  • Subtipos:
    • MEN2A: CMT, feocromocitoma, hiperparatiroidismo primário / adenoma da paratiroide
    • MEN2B ou MEN3: CMT, feocromocitoma, neuromas
• MEN4 MEN4 Multiple Endocrine Neoplasia:
  • Entidade relativamente recente
  • Semelhante à MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia
  • Tumores das glândulas paratiroides, da hipófise anterior e de células das ilhotas pancreáticas, em associação com tumores gonadais, suprarrenais, renais ou da tiroide.

Descrições gerais

MEN1

Síndrome MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia

• Conhecida anteriormente como síndrome de Wermer
• Geralmente envolve os 3 P‘s: glândulas Paratiroides, hipófise anterior (Pituitária) e células das ilhotas Pancreáticas

Etiologia e epidemiologia

• Genética:
  • Hereditariedade autossómica dominante
  • Mutação do gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia (codifica a proteína menina)
  • O gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics está localizado no braço longo do cromossoma 11 (11q13).
• Prevalência: 2 por 100.000 indivíduos
• Em 90% dos casos, a síndrome MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia é herdada de um dos progenitores, afetado pela doença.
• Os tumores neuroendócrinos pancreáticos (TNEs) surgem mais MAIS Androgen Insensitivity Syndrome precocemente quando associados ao MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia.

Fisiopatologia

• A proteína menina (codificada pelo gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia) regula a estabilidade do genoma, a proliferação e a apoptose.
• A mutação do gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics aumenta o risco de desenvolvimento de neoplasia.
• Em aproximadamente 10% dos indivíduos, ocorrem mutações de novo no MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia, que estão associadas à síndrome MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia não familiar / esporádica.

Apresentação clínica

• Origem endócrina:
  • Hiperparatiroidismo primário (95% dos casos):
    • ↑ Hormona da paratiroide (PTH), ↑ cálcio
    • “Stones (nefrolitíase), bones ( osteopenia Osteopenia Osteoporosis), abdominal groans (obstipação), and psychic moans (sintomas neuropsiquiátricos)”
  • TNEs enteropancreáticos (50% – 80%):
    • Gastrinoma Gastrinoma A gastrinoma is a tumor that secretes excessive levels of the hormone gastrin and is responsible for Zollinger-Ellison syndrome (ZES). Gastrinomas are frequently associated with multiple endocrine neoplasia 1 (MEN 1) and can arise from the pancreas, stomach, duodenum, jejunum, and/or even from the lymph nodes. Gastrinoma ( tumor Tumor Inflammation enteropancreático mais MAIS Androgen Insensitivity Syndrome comum): síndrome de Zollinger-Ellison (SZE), caracterizada por úlceras pépticas, refluxo e diarreia
    • Insulinoma Insulinoma A benign tumor of the pancreatic beta cells. Insulinoma secretes excess insulin resulting in hypoglycemia. Pancreatic Neuroendocrine Tumors (PanNETs): hipoglicemia
    • Glucagonoma Glucagonoma A glucagonoma is a glucagon-secreting neuroendocrine tumor that originates from the β-cells in the pancreatic islets. Most glucagonomas are malignant, and many of them are part of the autosomal dominant condition known as multiple endocrine neoplasia syndrome type 1 (MEN 1). Elevated levels of glucagon lead to increased gluconeogenesis and glycogenolysis. Glucagonoma: diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, eritema necrolítico migratório (ENM), anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types, trombose venosa profunda e sintomas neuropsiquiátricos
    • VIPoma VIPoma A VIPoma is a rare neuroendocrine tumor arising primarily in the pancreas that releases large amounts of vasoactive intestinal polypeptide (VIP). This process leads to chronic watery diarrhea with concomitant hypokalemia and dehydration, as well as wheezing and flushing (known as Verner-Morrison or WDHA syndrome). VIPoma: diarreia aquosa crónica, pieira e rubor Rubor Inflammation /flushing
    • Somatostatinoma Somatostatinoma A somatostatin-secreting tumor derived from the pancreatic delta cells (somatostatin-secreting cells). It is also found in the intestine. Somatostatinomas are associated with diabetes mellitus; cholelithiasis; steatorrhea; and hypochlorhydria. The majority of somatostatinomas have the potential for metastasis. Pancreatic Neuroendocrine Tumors (PanNETs): diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus, esteatorreia e colelitíase
  • Adenomas hipofisários (30% – 40%):
    • Prolactinoma Prolactinoma A pituitary adenoma which secretes prolactin, leading to hyperprolactinemia. Clinical manifestations include amenorrhea; galactorrhea; impotence; headache; visual disturbances; and cerebrospinal fluid rhinorrhea. Hyperprolactinemia (20%): hiperprolactinemia
    • Secretor de hormona do crescimento: acromegalia, gigantismo
    • Secretor de hormona adrenocorticotrófica (ACTH): doença de Cushing
  • Tumores carcinoides:
    • Tímico
    • Brônquico
    • Tumor Tumor Inflammation gástrico enterocromafim-like
  • Tumor Tumor Inflammation do córtex da suprarrenal (40%): não funcionante
• Origem não endócrina:
  • Lipoma Lipoma A lipoma is a benign neoplasm of fat cells (adipocytes) and the most common soft tissue tumor in adults. The etiology is unknown, but obesity is a predisposing factor; genetics also play a role, with multiple lipomas occurring in various inherited disorders. Lipoma
  • Angiofibroma Angiofibroma A benign neoplasm of fibrous tissue in which there are numerous small and large, frequently dilated, vascular channels. Tuberous Sclerosis
  • Colagenoma

Diagnóstico

• Os achados clínicos podem ser:
  • Ocorrência de ≥ 2 tumores primários MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia
  • História familiar de diagnóstico clínico de MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia + 1 tumor Tumor Inflammation primário associado a MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia
• Teste de DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure:
  • O benefício da testagem por rotina no MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia não é claro relativamente ao tratamento.
  • O diagnóstico é feito caso a caso:
    • Doente índice com MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia
    • Familiares de primeiro grau de portadores conhecidos da mutação do MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia
    • MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia atípico ou suspeito
• Rastreio dos restantes membros da família:
  • O hiperparatiroidismo primário é a característica mais MAIS Androgen Insensitivity Syndrome comum da síndrome MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia.
  • Os membros da família assintomáticos podem ser submetidos a testes Testes Gonadal Hormones opcionais menos dispendiosos:
    • Cálcio sérico
    • PTH
    • Níveis de vitamina D

Tratamento

• Tratamento:
  • Remoção dos tumores:
    • Paratiroidectomia
    • Excisão dos tumores pancreáticos e gástricos / entéricos
    • Cirurgia transesfenoidal para os tumores hipofisários
  • Inibidores da bomba de protões para os doentes com SZE
• Vigilância adicional para os membros da família assintomáticos com mutação no MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia confirmada (portadores de MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia):
  • Atentar nos sinais e sintomas de tumores associados a MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia
  • Monitorização anual dos níveis séricos de cálcio, PTH e prolactina
  • Imagem basal (neoplasia enteropancreática e tumores hipofisários) + follow-up
• Prognóstico:
  • Aproximadamente 30% dos doentes sucumbem a causas associadas ao MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia.
  • Os tumores endócrinos pancreáticos e carcinoides têm potencial maligno e contribuem para um maior risco de mortalidade nos doentes afetados.

Mnemónica

No sentido de recordar os locais de desenvolvimento de tumores na MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia, lembrar os 3 Ps PS Invasive Mechanical Ventilation:

• Pituitária
• Paratiroide
• Pâncreas

MEN2

Síndrome MEN2

• MEN2A:
  • Anteriormente conhecida como síndrome de Sipple
  • Variantes:
    • MEN2A clássico ( mais MAIS Androgen Insensitivity Syndrome comum): CMT, feocromocitoma, hiperparatiroidismo primário
    • MEN2A com Amiloidose cutânea liquenoide (CLA, pela sigla em inglês)
    • MEN2A com Doença de Hirschsprung ( HD HD Huntington disease (HD) is a progressive neurodegenerative disorder with an autosomal dominant mode of inheritance and poor prognosis. It is caused by cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin gene (htt). The most common clinical presentation in adulthood is a movement disorder known as chorea: abrupt, involuntary movements of the face, trunk, and limbs. Huntington Disease, pela sigla em inglês)
    • CMT familiar apenas
• MEN2B:
  • CMT, feocromocitoma
  • Associado ao fenótipo marfanoide, neuromas da mucosa (lábio, língua) e ganglioneuromas intestinais

Etiologia e Epidemiologia

• Genética:
  • Padrão de hereditariedade autossómico dominante
  • Mutação do proto-oncogene RET (reorganizado durante a transfecção) (que codifica para uma tirosina cinase transmembranar)
  • O gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics está localizado no cromossoma 10 (10q11.2).
• Prevalência de 1 em 30.000 indivíduos
• A MEN2B é menos comum, compreendendo apenas 5% – 6% dos casos de MEN2.

Fisiopatologia

• A ativação do RET leva à estimulação de múltiplas vias a jusante (envolvendo cinases) → crescimento e proliferação celular
• A MEN2 está associada à mutação de ganho de função do gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics RET.
• O risco de CMT depende do codão envolvido na mutação da linha germinativa:
  • A maioria das MEN2A: codão RET Cys634Arg
  • A maioria das MEN2B: codão RET Met918Thr (tem o maior risco de metástase precoce e de CMT agressivo)

Apresentação clínica

• MEN2A (clássico):
  • CMT (95% – 100%):
    • Massa ou adenopatia cervical
    • Pico de incidência na 3ª década de vida
  • Feocromocitoma (50%):
    • Hipertensão, taquicardia, cefaleias e hipersudorese
    • Idade média à apresentação: 25-32 anos
    • Pode ser bilateral
  • Hiperparatiroidismo primário (25%)
• MEN2 com CLA:
  • Lesões interescapulares ou extensoras descritas como papulares, descamativas e pruriginosas
  • Patologia: contém depósitos de amilóide
• MEN2 com HD HD Huntington disease (HD) is a progressive neurodegenerative disorder with an autosomal dominant mode of inheritance and poor prognosis. It is caused by cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin gene (htt). The most common clinical presentation in adulthood is a movement disorder known as chorea: abrupt, involuntary movements of the face, trunk, and limbs. Huntington Disease: megacólon aganglionar (ausência de células ganglionares autonómicas no cólon)
• MEN2B:
  • CMT (95% – 100%): apresenta-se numa idade ligeiramente mais MAIS Androgen Insensitivity Syndrome precoce relativamente ao MEN2A
  • Feocromocitoma (50%): semelhante à MEN2A
  • Neuromas da mucosa
  • Ganglioneuromas intestinais
  • Fenótipo marfanoide

Diagnóstico

• Suspeitar de MEN2 nos doentes que apresentam CMT, feocromocitoma ou tumores relacionados:
  • < 35 anos de idade
  • Lesões multicêntricas e / ou bilaterais
  • Para além da história familiar
• Testes Testes Gonadal Hormones para tumores específicos:
  • Feocromocitoma: metanefrinas plasmáticas fracionadas, depois TC da glândula suprarrenal
  • Hiperparatiroidismo: cálcio sérico, PTH
  • CMT: dosear a calcitonina sérica e realizar ecografia cervical e biópsia da tiroide na presença de uma massa
• Teste de DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure (análise da mutação do RET):
  • Em comparação com a MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia, o teste genético oferece um benefício claro para diagnosticar os membros da família (especialmente indivíduos em risco de CMT agressivo).
  • Indicações:
    • MEN2 confirmada clinicamente
    • Presença de um CMT ou feocromocitoma + um membro da família com uma destas doenças
    • Presença de CMT ou feocromocitoma ou tumores relacionados com características suspeitas (idade jovem, lesões multicêntricas, 2 órgãos diferentes afetados)
    • CMT esporádico
    • Familiares de primeiro e segundo grau de doentes com MEN2
• Se não houver mutação no RET ou padrão autossómico dominante:
  • São necessárias ≥ 2 características clínicas clássicas de MEN2A para o diagnóstico
  • Ou a maioria das características clínicas clássicas de MEN2B

Tratamento

• Princípios gerais:
  • Tratamento cirúrgico com base no(s) tumor Tumor Inflammation(es) que estão presentes:
    • Tiroidectomia
    • Adrenalectomia
    • Paratiroidectomia
  • No CMT:
    • O feocromocitoma deve ser excluído antes de qualquer cirurgia ser realizada.
    • Se existir um feocromocitoma, a adrenalectomia é realizada antes da tiroidectomia para evitar complicações fatais.
  • No feocromocitoma:
    • Antes da adrenalectomia, é recomendado o bloqueio alfa pré-operatório para prevenir uma crise hipertensiva.
    • Se for necessária uma adrenalectomia bilateral, são administrados glucocorticoides para evitar a insuficiência suprarrenal.
  • No hiperparatiroidismo é necessária monitorização após a cirurgia:
    • Para o hipoparatiroidismo
    • Para a lesão do nervo laríngeo superior ou recorrente
• Outras recomendações para os portadores da mutação do RET:
  • O risco de CMT depende da mutação do codão.
  • A tiroidectomia profilática depende do risco:
    • Mutação de alto risco (codão Met918Thr): cirurgia no primeiro ano de vida
    • Rastreio anual para os restantes doentes; o momento da cirurgia é dependente da idade.
  • Doseamento anual das metanefrinas fracionadas (prosseguir com a imagiologia se positivas)
  • Cálcio sérico (dosear a PTH se elevado)

Mnemónica

No sentido de recordar os locais de desenvolvimento de tumores na MEN2, lembrar os 3 Ps PS Invasive Mechanical Ventilation:

• MEN2A: 2 Ps PS Invasive Mechanical Ventilation
  • Paratiroide
  • Pheochromocytoma (Feocromocitoma)
• MEN2B: 1P
  • Pheochromocytoma (Feocromocitoma)

MEN4

Síndrome MEN4 MEN4 Multiple Endocrine Neoplasia

• Evidência limitada, sobretudo da última década
• Inicialmente denominado MENX em ratos
• Caracterizado por:
  • Tumores associados a MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia (adenomas das paratiroides, adenomas hipofisários e TNEs pancreáticos)
  • Com tumores gonadais, renais, tiroideus e suprarrenais

Etiologia e Epidemiologia

• Genética:
  • Padrão de hereditariedade autossómico dominante
  • Mutação do gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics inibidor da cinase dependente da ciclina CDKN1B
  • Encontrado no cromossoma 12p13
• Doentes com tumores MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia:
  • Aproximadamente 10% não têm a mutação do gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia.
  • Em cerca de 3% dos casos, o gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics envolvido é o CDKN1B.

Fisiopatologia

• Foram identificadas mutações de perda de função no CDKN1B em doentes com tumores MEN1-like.
• Resulta na redução da proteína do ponto de verificação do ciclo celular, p27 (regula a transcrição, inibindo a progressão do ciclo celular)
• Diminuição da função do p27 → instabilidade genómica, crescimento celular e proliferação não regulados

Apresentação clínica

• Adenoma da paratiroide (em aproximadamente 80% dos doentes)
• O adenoma hipofisário (em cerca de 37% dos doentes) pode variar entre:
  • Não funcional
  • Somatotropinoma
  • Prolactinoma Prolactinoma A pituitary adenoma which secretes prolactin, leading to hyperprolactinemia. Clinical manifestations include amenorrhea; galactorrhea; impotence; headache; visual disturbances; and cerebrospinal fluid rhinorrhea. Hyperprolactinemia
  • Corticotropinoma
• TNEs pancreáticos: menor penetrância que a MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia
• Tumores renais
• Alguns relatos mencionam tumores nos órgãos reprodutivos e nas suprarrenais.

Diagnóstico

• Estão em falta diretrizes definitivas, dada a raridade da doença e os poucos casos relatados.
• Oferecer testes Testes Gonadal Hormones genéticos aos doentes com mutações do CDKN1B que apresentam características de tumores MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia, mas são negativos para a mutação do MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia
• O teste genético pode também ser oferecido aos familiares em primeiro grau.

Tratamento

• Hiperparatiroidismo primário (adenoma): paratiroidectomia
• Adenoma hipofisário: cirurgia transesfenoidal se indicação
• Excisão dos TNEs pancreáticos
• Vigilância dos outros tumores

Relevância Clínica

• Hiperparatiroidismo: condição associada a níveis elevados de PTH no sangue. O hiperparatiroidismo pode ser classificado como primário, secundário ou terciário, com base na patogénese. O hiperparatiroidismo primário é uma doença da glândula paratireoide associada à secreção inapropriada de PTH. O hiperparatiroidismo secundário resulta do metabolismo anormal do cálcio, que, quando não tratado, pode progredir para o tipo terciário, que está associado à hipertrofia das paratiroides e à produção excessiva de PTH. O diagnóstico é baseado nos níveis séricos de PTH, cálcio e fosfato, e urinários de cálcio. A paratiroidectomia cirúrgica é realizada nos doentes com hiperparatiroidismo primário e terciário. O hiperparatiroidismo secundário requer tratamento da doença subjacente.
• Gastrinoma Gastrinoma A gastrinoma is a tumor that secretes excessive levels of the hormone gastrin and is responsible for Zollinger-Ellison syndrome (ZES). Gastrinomas are frequently associated with multiple endocrine neoplasia 1 (MEN 1) and can arise from the pancreas, stomach, duodenum, jejunum, and/or even from the lymph nodes. Gastrinoma: tumores que secretam gastrina e são responsáveis pelo SZE. Os gastrinomas estão associados à MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia. O tumor Tumor Inflammation, que geralmente é maligno, pode surgir no pâncreas, estômago, intestino delgado e/ou gânglios linfáticos. A síndrome de Zollinger-Ellison está associada a níveis elevados de gastrina e a produção de ácido gástrico excessiva, e manifesta-se por úlceras pépticas, refluxo gastroesofágico e diarreia. O diagnóstico baseia-se nos níveis de gastrina sérica em jejum. O tratamento envolve a resseção cirúrgica dos gastrinomas e/ou tratamento sintomático para a doença irressecável.
• Insulinoma Insulinoma A benign tumor of the pancreatic beta cells. Insulinoma secretes excess insulin resulting in hypoglycemia. Pancreatic Neuroendocrine Tumors (PanNETs): TNE que se manifesta por hipoglicemia causada pela secreção inadequadamente elevada de insulina. Os insulinomas Insulinomas An insulinoma is a type of functional neuroendocrine tumor that manifests with hypoglycemia due to autologous secretion of insulin. It more commonly presents as a solitary benign tumor but can sometimes be associated with MEN type 1 (MEN1). Patients present with fasting hypoglycemia, which may manifest as episodes of diaphoresis, palpitations, tremor, and confusion. Insulinomas apresentam-se sobretudo como um tumor Tumor Inflammation benigno solitário, mas por vezes podem estar associados à MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia. Os sintomas de hipoglicemia e de estimulação adrenérgica incluem palpitações, fraqueza, diaforese, alterações comportamentais, tremores e visão turva. O diagnóstico é baseado em testes Testes Gonadal Hormones bioquímicos. O tratamento de escolha é a resseção cirúrgica.
• Glucagonoma Glucagonoma A glucagonoma is a glucagon-secreting neuroendocrine tumor that originates from the β-cells in the pancreatic islets. Most glucagonomas are malignant, and many of them are part of the autosomal dominant condition known as multiple endocrine neoplasia syndrome type 1 (MEN 1). Elevated levels of glucagon lead to increased gluconeogenesis and glycogenolysis. Glucagonoma: tumor Tumor Inflammation secretor de glucagon Glucagon A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal glucagon-like peptides. Glucagon is secreted by pancreatic alpha cells and plays an important role in regulation of blood glucose concentration, ketone metabolism, and several other biochemical and physiological processes. Gastrointestinal Secretions que tem origem nas células α das ilhotas pancreáticas. A maioria dos glucagonomas é maligna e muitos fazem parte da MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia. Os níveis elevados de glucagon Glucagon A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal glucagon-like peptides. Glucagon is secreted by pancreatic alpha cells and plays an important role in regulation of blood glucose concentration, ketone metabolism, and several other biochemical and physiological processes. Gastrointestinal Secretions levam ao aumento da gluconeogénese e glicogenólise. Os doentes apresentam-se com diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, ENM, perda de peso, anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types, trombose venosa profunda e sintomas neuropsiquiátricos. O diagnóstico é baseado em análises laboratoriais que mostram níveis elevados de glucagon Glucagon A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal glucagon-like peptides. Glucagon is secreted by pancreatic alpha cells and plays an important role in regulation of blood glucose concentration, ketone metabolism, and several other biochemical and physiological processes. Gastrointestinal Secretions e em estudos de imagem revelando uma massa pancreática. O tratamento é geralmente de suporte e envolve a utilização de octreótido (um análogo da somatostatina). Na doença localizada é tentada a resseção cirúrgica. Nos casos avançados é usada a quimioterapia e os agentes moleculares direcionados.
• VIPoma VIPoma A VIPoma is a rare neuroendocrine tumor arising primarily in the pancreas that releases large amounts of vasoactive intestinal polypeptide (VIP). This process leads to chronic watery diarrhea with concomitant hypokalemia and dehydration, as well as wheezing and flushing (known as Verner-Morrison or WDHA syndrome). VIPoma: tumor Tumor Inflammation raro caracterizado pela hipersecreção de péptido intestinal vasoativo ( VIP VIP A highly basic, 28 amino acid neuropeptide released from intestinal mucosa. It has a wide range of biological actions affecting the cardiovascular, gastrointestinal, and respiratory systems and is neuroprotective. It binds special receptors. Gastrointestinal Neural and Hormonal Signaling). O tumor Tumor Inflammation nasce no pâncreas e manifesta-se por diarreia aquosa crónica com hipocaliémia e desidratação concomitantes, bem como pieira e flushing/ rubor Rubor Inflammation (conhecida como síndrome de Verner-Morrison ou DAHA). A maioria dos tumores são esporádicos, porém alguns associam-se à MEN1 MEN1 A form of multiple endocrine neoplasia that is characterized by the combined occurrence of tumors in the parathyroid glands, the pituitary gland, and the pancreatic islets. The resulting clinical signs include hyperparathyroidism; hypercalcemia; hyperprolactinemia; cushing disease; gastrinoma; and zollinger-ellison syndrome. This disease is due to loss-of-function of the men1 gene, a tumor suppressor gene on chromosome 11 (locus: 11q13). Multiple Endocrine Neoplasia. O diagnóstico baseia-se na determinação dos níveis séricos de VIP VIP A highly basic, 28 amino acid neuropeptide released from intestinal mucosa. It has a wide range of biological actions affecting the cardiovascular, gastrointestinal, and respiratory systems and is neuroprotective. It binds special receptors. Gastrointestinal Neural and Hormonal Signaling. O tratamento consiste no controlo médico dos sintomas e na remoção cirúrgica completa do tumor Tumor Inflammation.
• Adenoma hipofisário: tumor Tumor Inflammation que se desenvolve no lobo anterior da hipófise. Os adenomas hipofisários são classificados com base no tamanho como micro ou macroadenomas e com base na capacidade de secretar hormonas. Os adenomas não funcionantes ou não secretores não secretam hormonas, mas comprimem o tecido hipofisário circundante e levam ao hipopituitarismo. Os adenomas secretores produzem várias hormonas, dependendo do tipo de célula a partir da qual evoluíram e podem levar ao hiperpituitarismo.
• Tumor Tumor Inflammation carcinoide: TNE pequeno, bem diferenciado e de crescimento lento comummente encontrado no trato gastrointestinal e broncopulmonar. A síndrome carcinoide descreve os sinais e sintomas associados à produção desregulada de hormona vasoativo pelos tumores. As substâncias vasoativas produzidas pelo TNE GI não causam a síndrome carcinoide até os tumores metastizarem para o fígado. Os sintomas da síndrome carcinoide incluem flushing/ rubor Rubor Inflammation, diarreia e pieira. O tratamento envolve principalmente a resseção cirúrgica do tumor Tumor Inflammation e o uso de análogos da somatostatina.
• Cancro da tiroide: doença maligna que surge das células da tiroide e das células C produtoras de calcitonina (carcinomas medulares). As mutações driver envolvendo a via do recetor tirosina quinase, a história familiar de cancro ou de síndromes relacionadas e a radiação ionizante aumentam o risco. O cancro da tiroide pode apresentar-se como um nódulo tiroideu ou por gânglios linfáticos cervicais aumentados. O diagnóstico é feito através da determinação dos níveis da hormona estimuladora da tireoide (TSH), da ecografia e da biópsia. O tratamento inclui a tiroidectomia, com terapia com iodo radioativo e terapia sistémica, dependendo do tipo e extensão da neoplasia.
• Feocromocitoma: tumor Tumor Inflammation secretor de catecolaminas derivado das células cromafins, sendo que a maioria tem origem na medula da suprarrenal. Os feocromocitomas também podem surgir dos gânglios simpáticos (paragangliomas). A produção excessiva de catecolaminas pode causar hipertensão, taquicardia, cefaleias e hipersudorese. O diagnóstico é baseado no doseamento das metanefrinas fracionadas plasmáticas. A resseção cirúrgica é o único tratamento curativo.