RESUMO
Multiple endocrine neoplasia type 1 is a rare genetic neuroendocrine syndrome caused by over 1500 different germline mutations. It can cause 20 different endocrine tumors affecting primarily the parathyroid glands, gastroenteropancreatic tract, and the anterior pituitary gland. Multiple endocrine neoplasia type 2A (MEN2A) and Multiple endocrine neoplasia type 2B (MEN2B) are autosomal dominant genetic syndromes because of a germline variant in the 'rearranged during transfection' (RET) proto-oncogene. There are common RET mutations causing receptor hyperactivation and induction of downstream signals that cause oncogenesis. Common conditions with MEN2A are medullary thyroid cancer (MTC), pheochromocytoma, and primary hyperparathyroidism. Common conditions with MEN2B include MTC, pheochromocytomas, and benign ganglioneuromas.
Assuntos
Neoplasia Endócrina Múltipla Tipo 2a , Neoplasia Endócrina Múltipla Tipo 2b , Feocromocitoma , Proto-Oncogene Mas , Neoplasias da Glândula Tireoide , Humanos , Neoplasia Endócrina Múltipla Tipo 2a/diagnóstico , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/terapia , Neoplasia Endócrina Múltipla Tipo 2b/diagnóstico , Neoplasia Endócrina Múltipla Tipo 2b/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/terapia , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/terapia , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Neoplasia Endócrina Múltipla Tipo 1/terapia , Neoplasia Endócrina Múltipla Tipo 1/genética , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/terapia , Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/terapia , Atenção Primária à Saúde , Mutação em Linhagem Germinativa , Carcinoma NeuroendócrinoRESUMO
PURPOSE: No genomic data have been put forth that prove beyond a shadow of doubt that sporadic medullary thyroid cancer (MTC) occurs in infancy, childhood, and/or adolescence. METHODS: This was a retrospective comparative study of consecutive patients with MTC who had neck surgery at a tertiary center over a 30-year period. RESULTS: Included were 1252 patients with MTC (337 hereditary and 915 sporadic), of whom 107 (8.5%) were operated before the age of 18 yrs. Only 4 (3.7%) of the 107 pediatric patients, aged 14, 16, 17 and 17 years, had sporadic MTC. These 4 patients, 3 of whom had been referred for completion surgery, revealed much larger thyroid tumors (medians of 20 mm vs. 1.5-5 mm) than the 103 pediatric patients with hereditary MTC. As for extrathyroid extension and nodal metastases, the 4 patients with sporadic MTC were more comparable to the 37 carriers of highest-risk mutations, 31 (84%) of whom were index patients with de novo disease, than to the 66 carriers of high-risk, intermediate-risk, or low-risk RET mutations (25-38% vs. 0-8%, and medians of 9-9.5 vs. 0 node metastases after dissection of more (medians of 72-91.5 vs. 4.5-9) nodes). CONCLUSION: Sporadic MTC, arising rarely, if ever, below the age of 14 years, is exceptional in infancy and childhood, and infrequent in adolescence. At diagnosis, it is almost as widely metastatic as hereditary MTC of the highest-risk category which almost always, like sporadic MTC, presents as de novo disease.
Assuntos
Carcinoma Medular , Carcinoma Neuroendócrino , Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Adolescente , Estudos Retrospectivos , Masculino , Feminino , Criança , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Carcinoma Medular/genética , Carcinoma Medular/congênito , Carcinoma Medular/patologia , Pré-Escolar , Proteínas Proto-Oncogênicas c-ret/genética , Tireoidectomia , Lactente , Neoplasia Endócrina Múltipla Tipo 2a/genética , Adulto Jovem , MutaçãoRESUMO
Medullary thyroid carcinoma (MTC) accounts for only 3% of all thyroid carcinomas: 75% as sporadic MTC (sMTC) and 25% as hereditary MTC (hMTC) in the context of multiple endocrine neoplasia type 2 (MEN2). Early diagnosis is possible by determining the tumour marker calcitonin (Ctn) when clarifying nodular goitre and by detecting the mutation in the proto-oncogene RET in the MEN2 families. If the Ctn level is only slightly elevated, up to 30 pg/ml in women and up to 60 pg/ml in men, follow-up checks are advisable. At higher levels, surgery should be considered; at a level of > 100 pg/ml, surgery is always advisable. The treatment of choice is total thyroidectomy, possibly with central lymphadenectomy. In the early stage, cure is possible with adequate surgery; in the late stage, treatment with tyrosine kinase inhibitors is an option. RET A mutation analysis should be performed on all patients with MTC. During follow-up, a biochemical distinction is made between: healed (Ctn not measurably low), biochemically incomplete (Ctn increased without tumour detection) and structural tumour detection (metastases on imaging). After MTC surgery, the following results should be available for classification in follow-up care: (i) histology, Ctn immunohistology if necessary, (ii) classification according to the pTNM scheme, (iii) the result of the RET analysis for categorisation into the hereditary or sporadic variant and (iiii) the postoperative Ctn value. Tumour progression is determined by assessing the Ctn doubling time and the RECIST criteria on imaging. In most cases, "active surveillance" is possible. In the case of progression and symptoms, the following applies: local (palliative surgery, radiotherapy) before systemic (tyrosine kinase inhibitors).
Assuntos
Carcinoma Medular , Neoplasia Endócrina Múltipla Tipo 2a , Proto-Oncogene Mas , Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapia , Carcinoma Medular/genética , Carcinoma Medular/congênito , Carcinoma Medular/diagnóstico , Carcinoma Medular/patologia , Carcinoma Medular/terapia , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/diagnóstico , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Neoplasia Endócrina Múltipla Tipo 2a/terapia , Proteínas Proto-Oncogênicas c-ret/genética , Tireoidectomia , Mutação , Calcitonina/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/patologiaRESUMO
BACKGROUND: In clinical practice, genetic testing has become standard for many cancerous diseases. While a diagnosis of a single hereditary syndrome is not uncommon, the coexistence of two genetic diseases, even with partially common symptoms, remains unusual. Therefore, targeted next-generation sequencing (NGS), along with genetic consultation and imaging studies, is essential for every patient with confirmed paraganglioma. In this report, we present two sisters diagnosed with multiple endocrine neoplasia type 2 (MEN2A) and familial paraganglioma syndrome type 1 (FPGL1). CASE PRESENTATION: After presenting to the clinic with neck tumors persisting for several months, both patients underwent tumor removal procedures following imaging and laboratory studies. Pathological reports confirmed the diagnosis of paragangliomas. Subsequently, genetic testing, including NGS, revealed a mutation in the rearranged during transfection (RET) gene: the heterozygous change (c.2410G > A), (p.Val804Met), and a variant of the succinate dehydrogenase complex subunit D (SDHD) gene: (c.64 C > T), (p.Arg22Ter). Subsequently, thyroidectomy procedures were scheduled in both cases. CONCLUSION: To the best of our knowledge, this is the first report presenting these two mutations in two related patients, resulting in distinctive genetic syndromes with similar manifestations. This underscores that although infrequent, multiple hereditary disorders may co-occur in the same individual.
Assuntos
Neoplasia Endócrina Múltipla Tipo 2a , Irmãos , Succinato Desidrogenase , Humanos , Feminino , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/cirurgia , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Neoplasia Endócrina Múltipla Tipo 2a/diagnóstico , Succinato Desidrogenase/genética , Adulto , Proteínas Proto-Oncogênicas c-ret/genética , Prognóstico , Tireoidectomia , Mutação , Testes Genéticos , Linhagem , Paraganglioma/genética , Paraganglioma/cirurgia , Paraganglioma/diagnóstico , Paraganglioma/patologia , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
The age-specific development of the three constituent components of multiple endocrine neoplasia type 2 (MEN 2) is incompletely characterized for many of the >30 causative rearranged during transfection (RET) mutations, which this genetic association study aimed to specify. Included in the study were 683 carriers of heterogeneous RET germline mutations: 53 carriers with 1 highest-risk mutation (codon 918); 240 carriers with 8 different high-risk mutations (codon 634); 176 carriers with 16 different intermediate-risk mutations (codon 609, 611, 618, 620, or 630); and 214 carriers with 6 different low-risk mutations (codon 768, 790, 804, or 891).There was a strong genotype-specific development of MEN 2 constituent components, with distinct age gradients from C cell disease to node negative medullary thyroid cancer (MTC), from node negative to node positive MTC, from node positive MTC to pheochromocytoma, and from pheochromocytoma to primary hyperparathyroidism. Primary hyperparathyroidism was not observed among the 53 MEN 2B patients who carried highest-risk mutations (age range: 0.5-50 years), of whom no more than 12 (23%) and 3 (6%) carriers were older than age 30 years and 35 years, respectively. The age-specific development of MTC differed significantly between the four RET risk categories, whereas the age-specific development of pheochromocytoma differed significantly only between the two strongest RET risk categories. No significant differences were noted in the development of primary hyperparathyroidism. These findings delineate age-specific disease manifestation corridors for the three constituent components of MEN 2 by RET genotype. These corridors are useful for initial risk assessment and organ-specific surveillance of newly identified RET carriers going forward.
Assuntos
Neoplasias das Glândulas Suprarrenais , Genótipo , Neoplasia Endócrina Múltipla Tipo 2a , Feocromocitoma , Proteínas Proto-Oncogênicas c-ret , Neoplasias da Glândula Tireoide , Humanos , Proteínas Proto-Oncogênicas c-ret/genética , Pessoa de Meia-Idade , Adulto , Neoplasia Endócrina Múltipla Tipo 2a/genética , Adolescente , Masculino , Feminino , Neoplasias da Glândula Tireoide/genética , Adulto Jovem , Feocromocitoma/genética , Criança , Idoso , Pré-Escolar , Neoplasias das Glândulas Suprarrenais/genética , Lactente , Mutação em Linhagem Germinativa , Carcinoma Neuroendócrino/genética , Heterozigoto , Hiperparatireoidismo Primário/genética , Neoplasia Endócrina Múltipla Tipo 2b/genética , Idoso de 80 Anos ou maisRESUMO
Medullary thyroid cancer (MTC) is the most frequent manifestation of multiple endocrine neoplasia type 2 (MEN2) that determines the oncological outcome. Germline mutations in the rearranged during transfection (RET) protooncogene, a tumor suppressor gene on chromosome 10q11.2, were identified 30 years ago as the genetic basis of MEN2 and published in 1993 and 1994. These seminal findings gave rise to the concept of prophylactic thyroidectomy for asymptomatic gene mutation carriers based on a positive RET gene test, which has become the standard of care ever since. Clinical genetic investigations showed genotype-phenotype correlations with respect to the individual gene mutation regarding the penetrance and onset of MTC and to a lesser extent also with respect to the other components of MEN2, pheochromocytoma and primary hyperparathyroidism. From this a clinically relevant risk stratification could be derived. Initially, the optimal timing of prophylactic thyroidectomy was primarily based on the RET genotype alone, which was not sufficient for a precise age recommendation and subsequently required additional consideration of calcitonin serum levels for fine tuning. Calcitonin levels first show the risk of lymph node metastasis when they exceed the upper normal limit of the assay independent of carrier age and RET mutation. Routine calcitonin screening of patients with nodular thyroid disease, screening of families on identification of MEN2 index patients, and pre-emptive thyroidectomy in carriers of gene mutations with normal calcitonin levels have led to the fact that nowadays, 30 years after the first description of the gene mutations causing the disease, the life-threatening hereditary MTC has become curable: a shining example for the success of translational transnational medical research for the benefit of patients.
Assuntos
Neoplasia Endócrina Múltipla Tipo 2a , Proteínas Proto-Oncogênicas c-ret , Neoplasias da Glândula Tireoide , Tireoidectomia , Pesquisa Translacional Biomédica , Humanos , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/prevenção & controle , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/cirurgia , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Carcinoma Medular/genética , Carcinoma Medular/cirurgia , Carcinoma Medular/congênito , Carcinoma Medular/patologia , Procedimentos Cirúrgicos Profiláticos , Carcinoma Neuroendócrino/genéticaRESUMO
The report covers the current and past activities of the department Molecular Genetics-Function and Therapy (MGFT) at the Cyprus Institute of Neurology and Genetics (CING), an affiliated Reference Center for the European Reference Network on Rare Endocrine Conditions (Endo-ERN).The presented data is the outcome of > 15 years long standing collaboration between MGFT and endocrine specialists from the local government hospitals and the private sector. Up-to-date > 2000 genetic tests have been performed for the diagnosis of inherited rare endocrine disorders. The major clinical entities included Congenital Adrenal Hyperplasia (CAH) due to pathogenic variants in CYP21A2 gene and Multiple Endocrine Neoplasia (MEN) type 2 due to pathogenic variants in the RET proto-oncogene. Other rare and novel pathogenic variants in ANOS1, WDR11, FGFR1, RNF216, and CHD7 genes were also found in patients with Congenital Hypogonadotropic Hypogonadism. Interestingly, a few patients with Disorders of Sexual Differentiation (DSD) shared rare pathogenic variants in the SRD5A2, HSD17B3 and HSD3B2 while patients with Glucose and Insulin Homeostasis carried theirs in GCK and HNF1A genes. Lastly, MGFT over the last few years has established an esteemed diagnostic and research program on premature puberty with emphasis on the implication of MKRN3 gene on the onset of the disease and the identification of other prognosis biomarkers.As an Endo-ERN member MGFT department belongs to this large European network and holds the same humanistic ideals which aim toward the improvements of health care for patients with rare endocrine conditions in respect to improved and faster diagnosis.
Assuntos
Hiperplasia Suprarrenal Congênita , Doenças do Sistema Endócrino , Neoplasia Endócrina Múltipla Tipo 2a , Humanos , Chipre , Neoplasia Endócrina Múltipla Tipo 2a/diagnóstico , Neoplasia Endócrina Múltipla Tipo 2a/genética , Doenças do Sistema Endócrino/diagnóstico , Doenças do Sistema Endócrino/genética , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/genética , Testes Genéticos , Ubiquitina-Proteína Ligases , Esteroide 21-Hidroxilase/genética , Proteínas de Membrana/genética , 3-Oxo-5-alfa-Esteroide 4-DesidrogenaseRESUMO
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.
Assuntos
Doenças Inflamatórias Intestinais , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-ret , Feminino , Humanos , Idade de Início , Sequenciamento do Exoma , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/genética , Neoplasia Endócrina Múltipla Tipo 2a/genética , Mutação , Proteínas Proto-Oncogênicas c-ret/genética , LactenteRESUMO
BACKGROUND: Homozygous mutations, 2 identical gene versions (alleles), 1 from each biological parent, are exceptional. Clinical descriptions of affected families, comprising few carriers only, are scattered throughout the literature, hindering evidence generation. METHODS: Included in this literature analysis were 5 RET families with ≥1 homozygous carrier and ≥3 heterozygous carriers per family. RESULTS: In consanguineous families with first-degree cousins, homozygotes presented with node-positive medullary thyroid cancer and pheochromocytoma in their mid-teens, whereas heterozygotes presented in their end-30s and early 40s. Homozygotes developed node-positive medullary thyroid cancer 27.4 years and pheochromocytoma 23 years earlier than heterozygotes. These age differences were smaller in the 15 families carrying founder mutation p.Leu666delinsAsnSer, whereas homozygotes developed node-positive medullary thyroid cancer in their mid-40s, 6 years earlier than heterozygotes in their early 50s. CONCLUSION: These results, limited in scope and size and modulated by extent of consanguinity, are consistent with moderate dose-response effects accelerating MEN2A development.
Assuntos
Neoplasias das Glândulas Suprarrenais , Carcinoma Neuroendócrino , Neoplasia Endócrina Múltipla Tipo 2a , Feocromocitoma , Neoplasias da Glândula Tireoide , Adolescente , Humanos , Criança , Neoplasia Endócrina Múltipla Tipo 2a/genética , Feocromocitoma/genética , Homozigoto , Consanguinidade , Fenótipo , Proteínas Proto-Oncogênicas c-ret/genética , Linhagem , Neoplasias da Glândula Tireoide/genética , Neoplasias das Glândulas Suprarrenais/genéticaRESUMO
CONTEXT: Sporadic medullary thyroid carcinoma (sMTC) rarely occurs in childhood and no studies have specifically focused on this entity. OBJECTIVE: To describe the clinical presentations and long-term outcomes of a large cohort of children and young adults with sMTC compared with hereditary MTC (hMTC). METHODS: Retrospective study of 144 patients diagnosed with MTC between 1961 and 2019 at an age ≤â¯21 years and evaluated at a tertiary referral center. RESULTS: In contrast to hMTC (n = 124/144, 86%), patients with sMTC (n = 20/144, 14%) are older (P < .0001), have larger tumors (P < .0001), a higher initial stage grouping (P = .001) and have more structural disease (P = .0045) and distant metastases (DM) (P = .00084) at last follow-up, but are not more likely to die from MTC (P = .42). Among 77 patients diagnosed clinically, not by family history (20/20 sMTC and 57/124 hMTC), there was no difference in the initial stage (P = .27), presence of DM at diagnosis (P = 1.0), disease status at last follow-up (P = .13), overall survival (P = .57), or disease-specific survival (P = .87). Of the 12 sMTC tumors that underwent somatic testing, 11 (91%) had an identifiable alteration: 10 RET gene alterations and 1 ALK fusion. CONCLUSION: sMTC is primarily a RET-driven disease that represents 14% of childhood-onset MTC in this cohort. Pediatric sMTC patients are older, present with clinical disease at a more advanced TNM classification, and have more persistent disease at last follow-up compared with hMTC, but these differences disappear when comparing those presenting clinically. Somatic molecular testing should be considered in sMTC patients who would benefit from systemic therapy.
Assuntos
Carcinoma Neuroendócrino , Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/diagnóstico , Masculino , Feminino , Criança , Estudos Retrospectivos , Adolescente , Adulto Jovem , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/mortalidade , Pré-Escolar , Adulto , Seguimentos , Prognóstico , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Carcinoma Medular/genética , Carcinoma Medular/patologia , Carcinoma Medular/mortalidade , Carcinoma Medular/congênito , Carcinoma Medular/diagnóstico , LactenteRESUMO
Several genetic investigations were conducted to identify germline and somatic mutations in somatotropinomas, a subtype of pituitary tumors. To our knowledge, we report the first acromegaly patient carrying a RET pathogenic variant: c.2410G>A (rs79658334), p.Val804Met. Alongside the fact that the patient's father and daughter carried the same variant, we investigated the clinical significance of this variant in the context of somatotropinomas and other endocrine tumors, reviewing the RET mutations' oncogenic mechanisms. The aim was to search for new targets to precisely manage and treat acromegaly. Our case describes a new phenotype associated with the RET pathogenic variant, represented by aggressive acromegaly, and suggests consideration for RET mutation screening if NGS for well-established PitNET-associated gene mutations renders negative.
Assuntos
Acromegalia , Proteínas Proto-Oncogênicas c-ret , Humanos , Acromegalia/genética , Mutação em Linhagem Germinativa , Neoplasia Endócrina Múltipla Tipo 2a/genética , Mutação , Fenótipo , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/genéticaRESUMO
RET gain-of-function mutations are the most common drivers in medullary thyroid carcinoma, while RET fusions are identified in 5-10% of papillary thyroid carcinomas. Thus, RET plays a major role in the tumorigenesis of thyroid neoplasia, making it a valuable therapeutic target. Over a decade ago, multikinase inhibitors (MKIs) were first shown to have variable degrees of anti-RET activity. Despite some clinical efficacy in RET-altered thyroid cancers, significant off-target activity of MKIs led to marked toxicities limiting their use. More recently, two potent, highly selective RET inhibitors, selpercatinib and pralsetinib, were shown to have notable efficacy in RET-altered cancers, associated with more tolerable side effect profiles than those of MKIs. However, these treatments are non-curative, and emerging evidence suggests that patients who progress on therapy acquire mutations conferring drug resistance. Thus, the quest for a more definitive treatment for advanced, RET-altered thyroid cancers continues. This year we celebrate the 30th anniversary of the association of germline mutations of the RET proto-oncogene with the multiple endocrine neoplasia (MEN) type 2 syndromes. In this timely review, we summarize the current state-of-the-art treatment strategies for RET-altered thyroid cancers, their limitations, as well as future therapeutic avenues.
Assuntos
Carcinoma Neuroendócrino , Neoplasia Endócrina Múltipla Tipo 2a , Neoplasias da Glândula Tireoide , Humanos , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/patologia , Carcinoma Neuroendócrino/genética , Mutação , Mutação em Linhagem Germinativa , Neoplasia Endócrina Múltipla Tipo 2a/genética , Inibidores de Proteínas QuinasesRESUMO
An adult male in his early 30s diagnosed with multiple endocrine neoplasia type 2A syndrome, confirmed through genetic testing, presented as bilateral pheochromocytoma in a metachronous fashion, primary hyperparathyroidism and medullary thyroid carcinoma. Left and right adrenalectomy was done 9 years and 3 years ago, respectively. He was also subjected to total thyroidectomy with neck dissection and left inferior parathyroidectomy. During surveillance monitoring, 24-hour total urine metanephrines were elevated 13.977 mg (Normal value 0-1 mg) 1 year after right adrenalectomy. Adrenal CT scan demonstrated a 2.1 cm ovoid focus in the right suprarenal region, and functional imaging (131I meta-iodobenzylguanidine (MIBG scan) showed an avid uptake on the right frontal bone. Excision of the right adrenal bed and the right frontal bone tumour was performed, and metastatic pheochromocytoma was confirmed histologically. The patient achieved clinical and biochemical remission postoperatively and is currently receiving steroid and thyroxine replacement.
Assuntos
Neoplasias das Glândulas Suprarrenais , Neoplasia Endócrina Múltipla Tipo 2a , Feocromocitoma , Neoplasias da Glândula Tireoide , Adulto , Masculino , Humanos , Neoplasia Endócrina Múltipla Tipo 2a/complicações , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/cirurgia , Feocromocitoma/complicações , Feocromocitoma/cirurgia , Feocromocitoma/diagnóstico , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias da Glândula Tireoide/cirurgia , Glândulas Suprarrenais/patologia , Adrenalectomia , 3-IodobenzilguanidinaRESUMO
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.
Assuntos
Mutação em Linhagem Germinativa , Mosaicismo , Neoplasia Endócrina Múltipla Tipo 2a , Linhagem , Proteínas Proto-Oncogênicas c-ret , Humanos , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Proteínas Proto-Oncogênicas c-ret/genética , Mutação em Linhagem Germinativa/genética , Feminino , Masculino , Adulto , Substituição de Aminoácidos , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Genótipo , Sequenciamento do ExomaRESUMO
PURPOSE: Multiple endocrine neoplasia types 1 (MEN1) and 2 (MEN2) are inherited endocrine tumor syndromes caused by mutations in the MEN1 or RET genes. This study aimed to investigate clinical outcomes and molecular characteristics among children with MEN. METHODS: This study included eight patients from seven unrelated families. Data on clinical course, biochemical findings, and radiologic studies were collected by retrospective chart review. All diagnoses were genetically confirmed by Sanger sequencing of MEN1 in three MEN1 patients and RET in four patients with MEN2A and one patient with MEN2B. RESULTS: Three patients with MEN1 from two families presented with hypoglycemia at a mean age of 11±2.6 years. Four patients with MEN2A were genetically diagnosed at a mean of 3.0±2.2 years of age by family screening; one of them was prenatally diagnosed by chorionic villus sampling. Three patients with MEN2A underwent prophylactic thyroidectomy from 5 to 6 years of age, whereas one patient refused surgery. The patient with MEN2B presented with a tongue neuroma and medullary thyroid carcinoma at 6 years of age. Subsequently, he underwent a subtotal colectomy because of bowel perforation and submucosal ganglioneuromatosis at 18 years of age. CONCLUSION: This study described the relatively long clinical course of pediatric MEN with a mean follow-up duration of 7.5±3.8 years. Insulinoma was the first manifestation in children with MEN1. Early diagnosis by family screening during the asymptomatic period enabled early intervention. The patient with MEN2B exhibited the most aggressive clinical course.
Assuntos
Neoplasia Endócrina Múltipla Tipo 1 , Neoplasia Endócrina Múltipla Tipo 2a , Neoplasia Endócrina Múltipla Tipo 2b , Neoplasias da Glândula Tireoide , Masculino , Humanos , Adolescente , Criança , Neoplasia Endócrina Múltipla Tipo 2a/diagnóstico , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2b/diagnóstico , Neoplasia Endócrina Múltipla Tipo 2b/genética , Estudos Retrospectivos , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/terapia , Progressão da DoençaRESUMO
PURPOSE OF REVIEW: Significant advances have transformed our understanding of the molecular biology and natural history of multiple endocrine neoplasia type 2 (MEN2). This progress enacted a paradigm shift with regard to routine neck dissection for medullary thyroid cancer and total adrenalectomy for pheochromoytoma. The purpose of this review is to summarize key molecular and clinical data underpinning the current risk-based approach to MEN2 that integrates molecular and biomarker results. RECENT FINDINGS: Early identification and biochemical monitoring of rearranged during transfection ( RET ) carriers yield important lead time. Within these ' windows of opportunity ', total thyroidectomy alone, avoiding incremental morbidity from node dissection; ' tissue-sparing ' subtotal adrenalectomy, balancing risks of steroid dependency with pheochromocytoma recurrence in adrenal remnants; and parathyroidectomy of enlarged glands only, weighing risks of postoperative hypoparathyroidism against hyperactive parathyroid glands left behind, are adequate therapies. SUMMARY: All that is needed to determine a RET carriers' risk of medullary thyroid cancer, pheochromocytoma and/or primary hyperparathyroidism in the molecular era is patient age, underlying RET mutation, and biomarker levels. As broader testing begins to penetrate healthcare, the needle on population genomic screening and education needs to be moved forward to complete the transition from symptom-based to preventive healthcare.
Assuntos
Neoplasias das Glândulas Suprarrenais , Neoplasia Endócrina Múltipla Tipo 2a , Feocromocitoma , Neoplasias da Glândula Tireoide , Humanos , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/diagnóstico , Neoplasia Endócrina Múltipla Tipo 2a/cirurgia , Feocromocitoma/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/cirurgia , Biomarcadores , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/cirurgia , Tireoidectomia/métodosAssuntos
Carcinoma Neuroendócrino , Neoplasia Endócrina Múltipla Tipo 2a , Neoplasias da Glândula Tireoide , Humanos , Carcinoma Neuroendócrino/genética , Neoplasias da Glândula Tireoide/genética , Mutação em Linhagem Germinativa , Neoplasia Endócrina Múltipla Tipo 2a/genética , Proteínas Proto-Oncogênicas c-ret/genéticaRESUMO
PURPOSE: Differences in syndromic manifestations of multiple endocrine neoplasia 2 A (MEN2A) between index and non-index patients are ill-defined. METHODS: Cross-sectional analysis of 602 REarranged during Transfection (RET) carriers (156 index and 446 non-index patients) who underwent thyroidectomy, adrenalectomy, and/or parathyroidectomy between 1985 and 2022, stratified by mutational risk. RESULTS: Index patients were 5.8-13.9 years older at thyroidectomy than non-index patients, at which point they had developed 10.6-14.4 mm larger medullary thyroid cancers. Correlations between index status and primary tumor size (ρ = 0.489-0.544) were stronger than correlations between index status and age at thyroidectomy (ρ = 0.359-0.438). For pheochromocytoma and primary hyperparathyroidism, no significant differences were noted. When stratified by time of surgery before vs. in the new millennium, age at thyroidectomy fell significantly only for non-index patients in the new millennium: from 28.6 to 21.2 years (moderate-high risk mutations; P = 0.049) and from 23.1 to 12.3 years (high-risk mutations; P < 0.001). All other inter-millennium comparisons did not reach statistical significance. CONCLUSION: These findings imply that differences between index and non-index patients impact the first syndromic manifestation without extending to subsequent syndromic manifestations. Because they exhibited similar age and tumor characteristics for the secondary and tertiary manifestations of MEN2A, screening for these syndromic components remains an integral element of MEN2A management in index and non-index patients alike. Wider use of population genomic screening may work to diminish the observed disparities between index and non-index patients going forward.
Assuntos
Neoplasias das Glândulas Suprarrenais , Neoplasia Endócrina Múltipla Tipo 2a , Feocromocitoma , Neoplasias da Glândula Tireoide , Humanos , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/cirurgia , Estudos Transversais , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/cirurgia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/cirurgia , Mutação , Tireoidectomia , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/cirurgiaRESUMO
PURPOSE: Multiple endocrine neoplasia Type 2A (MEN2A) can occur with Hirschsprung disease (HD) due to mutation in the RET proto-oncogene, with the majority developing medullary thyroid carcinoma (MTC). Given the comorbidity, many parents have contacted us to share concerns and unfortunate experiences about the prevalence rates of MEN2A/MTC in patients with HD. The aim is to determine the prevalence rate of patients with HD and MEN2A or medullary thyroid carcinoma, respectively. METHODS: This is a cross-sectional study of the COSMOS database from January 01, 2017, to March 08, 2023. The database was searched for patients diagnosed with MEN2A, MTC, and HD. IRB exemption was provided (COMIRB #23-0526). RESULTS: The database contained 183,993,122 patients from 198 contributing organizations. The prevalence of HD and MEN2A was 0.00002%, and for HD and MTC was 0.000009%. One in 66 patients (1.5%) with MEN2A also had HD. One in 319 patients (0.3%) in the HD group had MEN2A. One in 839 patients (0.1%) within the HD population had MTC. CONCLUSION: The prevalence of MTC and HD or MEN2A and HD in the study population was low. Considering that almost all MEN2A patients have a positive family history, this data does not support the general genetic testing of HD patients.
Assuntos
Doença de Hirschsprung , Neoplasia Endócrina Múltipla Tipo 2a , Neoplasias da Glândula Tireoide , Humanos , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Doença de Hirschsprung/epidemiologia , Doença de Hirschsprung/genética , Incidência , Estudos Transversais , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/genéticaRESUMO
RATIONALE: Pheochromocytomas are a group of tumors with high genetic heterogeneity, and the clinical characteristics of rearranged during transfection (RET)-mutated pheochromocytoma with medullary spongiform kidney are rarely studied. The treatment process of 1 patient with bilateral adrenal pheochromocytoma combined with medullary sponge kidney with RET gene mutation in our department was retrospectively analyzed, and the treatment methods for this type of disease were studied and summarized in combination with relevant literature. PATIENT CONCERNS: In this case, the patient was found to have bilateral adrenal masses for 8 years due to physical examination, and intermittent dizziness and discomfort for 2 years. Imaging and related laboratory examinations suggest bilateral adrenal giant pheochromocytoma with bilateral medullary sponge kidney. RET gene testing was performed on the patient and his descendant after signing the informed consent form. DIAGNOSES: The patient was diagnosed with bilateral adrenal pheochromocytoma with a RET proto-oncogene mutation and a bilateral medullary spongy kidney. INTERVISION AND OUTCOMES: After sufficient perioperative preparation, retroperitoneal laparoscopic bilateral adrenal pheochromocytoma resection was performed by stages. The operation was successful, and hormone replacement therapy was performed after the operation, with regular follow-up. Relevant genetic testing revealed that the c.1900T > C: p.C634R mutation was detected in the patient's RET gene, which was a heterozygous missense mutation, and the mutation was also present in the son of his family. A literature analysis found that pheochromocytoma is a tumor with high genetic heterogeneity, and the RET proto-oncogene is a common pathogenic gene for bilateral adrenal pheochromocytoma. Medullary sponging of kidneys is a rare complication of this disease. LESSONS: On the basis of adequate perioperative preparation, surgical resection is the most effective and preferred treatment for this type of disease. Laparoscopic surgery is minimally invasive, safe, and effective by stages. Mutations in the RET proto-oncogene may lead to medullary spongy kidneys in multiple endocrine neoplasia 2.