RESUMEN
PURPOSE: We aimed to assess the definition of actionability of secondary findings in childhood, using a screening framework. METHODS: For 31 disorders on the American College of Medical Genetics and Genomics SF v.2.0 list, World Health Organization screening criteria were applied to assess actionability in childhood. RESULTS: The age of onset was variable. We categorized disorders based on the proportion of cases that presented in childhood: rare (n = 6), fewer than half the cases (n = 9), the majority of cases (n = 12), or unclear (n = 4). The age at initiation of intervention was based on the youngest age of onset reported, not evidence of the benefit of early intervention. For 15 disorders, guidelines were supported by a moderate quality of evidence for at least one recommendation. Only tuberous sclerosis complex had recommendations based on high-quality evidence. All others were based on evidence of low or very low quality. CONCLUSION: We propose that actionability in childhood should be based on the proportion of cases that manifest in childhood and the quality of the evidence supporting intervention recommendations. Ideally, disclosure in childhood would be limited to disorders for which a majority of cases present in childhood and for which interventions are supported by evidence of at least moderate quality (i.e., multiple endocrine neoplasia type 2, retinoblastoma, tuberous sclerosis complex, Marfan syndrome, and Wilson's disease).
Asunto(s)
Enfermedades Genéticas Congénitas/genética , Pruebas Genéticas , Genoma Humano/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Adolescente , Niño , Femenino , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/patología , Genómica , Degeneración Hepatolenticular/diagnóstico , Degeneración Hepatolenticular/epidemiología , Degeneración Hepatolenticular/genética , Humanos , Masculino , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/epidemiología , Síndrome de Marfan/genética , Neoplasia Endocrina Múltiple Tipo 2a/diagnóstico , Neoplasia Endocrina Múltiple Tipo 2a/epidemiología , Neoplasia Endocrina Múltiple Tipo 2a/genética , Retinoblastoma/diagnóstico , Retinoblastoma/epidemiología , Retinoblastoma/genética , Esclerosis Tuberosa/diagnóstico , Esclerosis Tuberosa/epidemiología , Esclerosis Tuberosa/genéticaRESUMEN
Although already 25 years into the genomic era, age-related progression of hereditary medullary thyroid cancer (MTC), the prevalence of which is estimated at one in 80,000 inhabitants, remains to be delineated for most unique RET (REarranged during Transfection) mutations. Included in this study were 567 RET carriers. The age-related progression of MTC across histopathological groups (normal thyroid/C-cell hyperplasia; node-negative MTC; node-positive MTC) was statistically significant for 13 unique RET mutations (p.Cys611Phe/c.1832G > T; p.Cys611Tyr; p.Cys618Ser/c.1852T > A; p.Cys620Arg; p.Cys634Arg; p.Cys634Phe; p.Cys634Ser; p.Cys634Tyr; p.Glu768Asp; p.Leu790Phe/c.2370G > T; p.Val804Met; p.Ser891Ala; p.Met918Thr), whereas two unique RET mutations (p.Cys618Phe; p.Cys634Gly) trended toward statistical significance. When grouped by mutational risk (highest; high; moderate-high; low-moderate; polymorphism), the age-related progression of MTC was significant for all four categories of RET mutations, which differed significantly across and within the three histopathological groups. For high, for moderate-high, and for low-moderate risk RET mutations, the age-related progression of MTC by mutated codon was broadly comparable across and within the three histopathological groups, and essentially unaffected by the amino acid substitutions examined. These data argue in favor of splitting the American Thyroid Association's moderate-risk category into moderate-high and low-moderate risk categories, while emphasizing the need to contradistinguish the latter from rare nonpathogenic polymorphisms.
Asunto(s)
Sustitución de Aminoácidos/genética , Carcinoma Medular/congénito , Mutación de Línea Germinal/genética , Neoplasia Endocrina Múltiple Tipo 2a/genética , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias de la Tiroides/genética , Adulto , Carcinoma Medular/epidemiología , Carcinoma Medular/genética , Carcinoma Medular/patología , Progresión de la Enfermedad , Femenino , Genotipo , Heterocigoto , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 2a/epidemiología , Neoplasia Endocrina Múltiple Tipo 2a/patología , Mutación , Linaje , Fenotipo , Proto-Oncogenes Mas , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/patologíaRESUMEN
PURPOSE: Multiple endocrine neoplasia type 2 (MEN2) affects patients with RET proto-oncogene mutations. This cohort study refers to patients who were diagnosed with familial medullary thyroid carcinoma (MTC) and underwent RET genetic testing in Cyprus between years 2002 and 2017. METHODS AND PATIENTS: Forty patients underwent RET testing by Sanger sequencing of exons 10-11 and 13-16. Genotyping with STR genetic markers flanking the RET gene along with Y-chromosome genotyping and haplogroup assignment was also performed. RESULTS: RET mutations were identified in 40 patients from 11 apparently unrelated Cypriot families and two non-familial sporadic cases. Nine probands (69.2%) were heterozygous for p.Cys618Arg, one (7.7%) for p.Cys634Phe, one (7.7%) for the somatic delE632-L633 and two (15.4%) for p.Met918Thr mutations. The mean age at MTC diagnosis of patients carrying p.Cys618Arg was 36.8 ± 14.2 years. The age of pheo diagnosis ranged from 26 to 43 years and appeared simultaneously with MTC in 5/36 (13.9%) cases. The high frequency of the p.Cys618Arg mutation suggested a possible ancestral mutational event. Haplotype analysis was performed in families with and without p.Cys618Arg. Six microsatellite markers covering the RET gene and neighboring regions identified one core haplotype associated with all patients carrying p.Cys618Arg mutation. CONCLUSIONS: The mutation p.Cys618Arg is by far the most prevalent mutation in Cyprus followed by other reported mutations of variable clinical significance. The provided molecular evidence speculates p.Cys618Arg mutation as an ancestral mutation that has spread in Cyprus due to a possible founder effect.
Asunto(s)
Carcinoma Medular/congénito , Efecto Fundador , Neoplasia Endocrina Múltiple Tipo 2a/epidemiología , Neoplasia Endocrina Múltiple Tipo 2a/genética , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/genética , Adulto , Arginina/genética , Carcinoma Medular/diagnóstico , Carcinoma Medular/epidemiología , Carcinoma Medular/genética , Estudios de Cohortes , Chipre/epidemiología , Cisteína/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 2a/diagnóstico , Linaje , Proto-Oncogenes Mas , Neoplasias de la Tiroides/diagnósticoRESUMEN
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from the thyroid C cells producing mainly calcitonin (CTN) used as tumor marker. MTC occurs either sporadic (75%) or in a hereditary form (multiple endocrine neoplasia type 2, MEN2), due to germline mutations in the RET proto-oncogene. The discovery of an MTC in a patient has several diagnostic implications involving a specific strategy: preoperative evaluation of the tumor marker CTN and the extent of the disease, classification of MTC as sporadic or hereditary by DNA testing, and screening for associated endocrinopathies in hereditary MTC. Elevated CTN is a highly sensitive and specific tumor marker for diagnosis and follow-up of MTC. CTN is directly related to the tumor mass. In patients with nodular thyroid disease, diagnosis of MTC could be made by CTN determination as an indicator of tumor burden in conjunction with fine-needle aspiration. Patients with confirmed sporadic or hereditary MTC should have a total thyroidectomy and depending on the preoperative CTN value and the extent of disease additional dissection of the lymph nodes in the central and lateral neck compartment. In MEN 2 patients diagnosed by screening, the time of prophylactic thyroidectomy depends on RET mutation and CTN level.
Asunto(s)
Carcinoma Neuroendocrino/diagnóstico , Carcinoma Neuroendocrino/epidemiología , Neoplasia Endocrina Múltiple Tipo 2a/diagnóstico , Neoplasia Endocrina Múltiple Tipo 2a/epidemiología , Neoplasia Endocrina Múltiple Tipo 2b/diagnóstico , Neoplasia Endocrina Múltiple Tipo 2b/epidemiología , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/epidemiología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/metabolismo , Carcinoma Neuroendocrino/terapia , Citodiagnóstico , Diagnóstico por Imagen , Predisposición Genética a la Enfermedad , Humanos , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/metabolismo , Neoplasia Endocrina Múltiple Tipo 2a/terapia , Neoplasia Endocrina Múltiple Tipo 2b/genética , Neoplasia Endocrina Múltiple Tipo 2b/metabolismo , Neoplasia Endocrina Múltiple Tipo 2b/terapia , Estadificación de Neoplasias , Fenotipo , Valor Predictivo de las Pruebas , Proto-Oncogenes Mas , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/terapia , Tiroidectomía , Resultado del TratamientoRESUMEN
INTRODUCTION: Papillary thyroid carcinoma (PTC) is exceptional in MEN 2. RESULTS: The analysis in 135 patients revealed two PTC, without C-cell pathology; both being positive for V804M mutation (RET proto-oncogene). CONCLUSIONS: Few data are available about PTC in MEN 2, and without C-cell pathology is even less common. More studies are needed to correlate genetics and histology, and even for assessing PTC as only manifestation of MEN 2.
Asunto(s)
Carcinoma Medular/genética , Carcinoma/genética , Neoplasia Endocrina Múltiple Tipo 2a/genética , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias de la Tiroides/genética , Adulto , Carcinoma/epidemiología , Carcinoma Medular/epidemiología , Carcinoma Papilar , Comorbilidad , Femenino , Humanos , Masculino , Neoplasia Endocrina Múltiple Tipo 2a/epidemiología , Mutación , Proto-Oncogenes Mas , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/epidemiologíaRESUMEN
Primary hyperparathyroidism is a heterogeneous clinical entity. In the clinical setting, the diagnosis and management of familial isolated hyperparathyroidism (FIHP) and other familial hyperparathyroidism (FHPT) forms continue to rely on clinical, laboratory, and histological findings, with careful examination of the family. In this article, we report a case series of FIHP in a four-generation Greek family, with no identifiable gene mutations. Clinical approach and long-term follow-up are discussed and a narrative review of the genetic basis of this entity has been performed.
Asunto(s)
Hiperparatiroidismo/genética , Adulto , Anciano , Femenino , Humanos , Hiperparatiroidismo/epidemiología , Hiperparatiroidismo Primario/epidemiología , Hiperparatiroidismo Primario/genética , Masculino , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 1/epidemiología , Neoplasia Endocrina Múltiple Tipo 1/genética , Neoplasia Endocrina Múltiple Tipo 2a/epidemiología , Neoplasia Endocrina Múltiple Tipo 2a/genética , Linaje , Población Blanca , Adulto JovenRESUMEN
Primary hyperparathyroidism is a common endocrine disorder, resulting from a persistent hypercalcemia along with an inadequate secretion of parathyroid hormone. In approx 95% of cases, it occurs sporadically; rarely, it is part of familial syndromes. These inherited syndromes typically present at an earlier age than the nonheritable form and occur with equal frequencies in both sexes. The differential diagnosis is often difficult, but it is of fundamental importance for the management of patients and their family. The availability of specific genetic tests has improved the diagnostic accuracy allowing early diagnosis in asymptomatic family members. Before the advent of genetic testing, a definitive diagnosis could be made only in symptomatic cases based on clinical data and family history.
Asunto(s)
Hiperparatiroidismo/epidemiología , Humanos , Hiperparatiroidismo/diagnóstico , Neoplasia Endocrina Múltiple/epidemiología , Neoplasia Endocrina Múltiple Tipo 1/epidemiología , Neoplasia Endocrina Múltiple Tipo 2a/epidemiología , SíndromeRESUMEN
AIM: Calcitonin (Ctn) measurement in patients with thyroid disease could potentially increase the detection rates of medullary thyroid carcinoma (MTC) but remains a controversial issue. The aim of this study was to evaluate routine preoperative Ctn measurements. METHODS: All patients with thyroid surgery documented in the prospective StuDoQ|Thyroid registry between March 2017 and September 2020 were included. Cutoff levels for Ctn were determined with receiver-operating characteristic analyses to assess the preoperative diagnosis of MTC in subgroups for females and males. FINDINGS: In 29 590 of 39 679 patients (75%) participating in the registry, routine preoperative Ctn testing was performed. In 357 patients (227 females and 130 males), histopathology confirmed MTC with a mean tumor size of 14.7 mm (±12.43). Biochemical cure was achieved in 71.4% of the patients. Ctn levels between 11 and 20 pg/mL were seen in 2.6% of the patients, and only 0.7% of the patients had Ctn levels above 21 pg/mL. Cutoff levels for the diagnosis of MTC were 7.9 pg/mL for females and 15 pg/mL for males (P < 0.001). The sensitivity and specificity for females were 95 and 98%, and 96 and 97% for males, respectively. CONCLUSION: Routine Ctn testing is a reliable predictor for MTC and provides the opportunity for earlier thyroidectomy before lymph node metastases occur, resulting in a better prognosis. Females with Ctn levels >7.9 pg/mL and males >15 pg/mL without any other extrathyroidal sources for an elevated Ctn should be monitored. Thyroid surgery should be considered if Ctn levels are increasing or ultrasound detects suspicious thyroid lesions.
Asunto(s)
Biomarcadores de Tumor/sangre , Calcitonina/sangre , Carcinoma Neuroendocrino/sangre , Periodo Preoperatorio , Enfermedades de la Tiroides/cirugía , Neoplasias de la Tiroides/sangre , Adulto , Anciano , Anciano de 80 o más Años , Austria/epidemiología , Carcinoma Neuroendocrino/patología , Carcinoma Neuroendocrino/cirugía , Femenino , Alemania/epidemiología , Humanos , Metástasis Linfática/patología , Masculino , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 2a/epidemiología , Pronóstico , Valores de Referencia , Sensibilidad y Especificidad , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/cirugía , UltrasonografíaRESUMEN
Neuroendocrine tumors (NETs) can be sporadic or they can arise in complex hereditary syndromes. Patients with hereditary NETs can be identified before the development of tumors by performing genetic screenings. The aim of the study was to evaluate the clinical and prognostic impact of a preclinical genetic screening in subjects with hereditary NET syndromes. 46 subjects referred for hereditary NET syndrome [22 MEN1, 12 MEN2, 12 Familial Paragangliomatosis (FPGL)] were enrolled and divided in 2 groups (group A, 20 subjects with clinical appearance of NET before the genetic diagnosis; group B, 26 subjects with genetic diagnosis of hereditary NET syndromes before the clinical appearance of NETs). The main outcome measures were severity of disease, prognosis, and survival. The rate of surgery for MEN1-, MEN2-, FPGL4-related tumors was 90% in group A and 35% in group B (p<0.01). Both symptoms related to tumors and symptoms related to therapies were significantly less frequent in group B than in group A (p<0.05). Tumor stage was locally advanced or metastatic in 50% of group A and in no one of group B (p<0.01). The mortality rate was 25% in group A and 0% in group B (p<0.05). An early genetic screening for hereditary NET syndromes results in an improvement in clinical presentation and morbidity. A potential impact of the genetic screening on the mortality rate of these subjects is suggested and needs to be investigated in further and more appropriate studies.
Asunto(s)
Pruebas Genéticas , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/fisiopatología , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/fisiopatología , Detección Precoz del Cáncer , Salud de la Familia , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Hospitales Universitarios , Humanos , Italia/epidemiología , Masculino , Neoplasia Endocrina Múltiple Tipo 1/diagnóstico , Neoplasia Endocrina Múltiple Tipo 1/epidemiología , Neoplasia Endocrina Múltiple Tipo 1/genética , Neoplasia Endocrina Múltiple Tipo 1/fisiopatología , Neoplasia Endocrina Múltiple Tipo 2a/diagnóstico , Neoplasia Endocrina Múltiple Tipo 2a/epidemiología , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/fisiopatología , Estadificación de Neoplasias , Síndromes Neoplásicos Hereditarios/epidemiología , Síndromes Neoplásicos Hereditarios/genética , Tumores Neuroendocrinos/epidemiología , Tumores Neuroendocrinos/genética , Paraganglioma/diagnóstico , Paraganglioma/epidemiología , Paraganglioma/genética , Paraganglioma/fisiopatología , Prevalencia , Pronóstico , Calidad de Vida , Análisis de SupervivenciaRESUMEN
Activating variants in the receptor tyrosine kinase REarranged during Transfection (RET) cause multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominantly inherited cancer-susceptibility syndrome. The variant c.166C>A, p.Leu56Met in RET was recently reported in two patients with medullary thyroid cancer (MTC). The presence of a pheochromocytoma in one of the patients, suggested a possible pathogenic role of the variant in MEN 2A. Here, we present clinical follow up of a Danish RET Leu56Met cohort. Patients were evaluated for signs of MEN 2 according to a set of predefined criteria. None of the seven patients in our cohort exhibited evidence of MEN 2. Furthermore, we found the Leu56Met variant in our in-house diagnostic cohort with an allele frequency of 0.59%, suggesting that it is a common variant in the population. Additionally, none of the patients who harbored the allele were listed in the Danish MTC and MEN 2 registries. In conclusion, our findings do not support a pathogenic role of the Leu56Met variant in MEN 2.
Asunto(s)
Variación Genética/genética , Mutación de Línea Germinal/genética , Leucina/genética , Metionina/genética , Neoplasia Endocrina Múltiple Tipo 2a/genética , Proteínas Proto-Oncogénicas c-ret/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Dinamarca/epidemiología , Femenino , Pruebas Genéticas/métodos , Humanos , Masculino , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 2a/diagnóstico , Neoplasia Endocrina Múltiple Tipo 2a/epidemiologíaRESUMEN
BACKGROUND Multiple endocrine neoplasia type 2 (MEN 2) is caused by a RET mutation in chromosome 10. All MEN 2 patients develop medullary thyroid carcinoma (MTC). The age-related risk of MTC is associated with the type of RET mutation. Our aim was to identify prognostic factors associated with recurrent MTC in MEN 2 patients. METHODS In a nationwide case-control study, all patients who underwent total thyroidectomy in the Netherlands under the age of 20 years were classified into standard (1), high (2), or very high risk (3) for MTC based on RET-mutation type. Disease-free patients were compared with those with recurrent disease. RESULTS A total of 93 patients were included in the study. Sixty-six percent had MTC on histology, the youngest being 1 year old. Codon 634 was most affected. Sixteen (18%) patients had persistent or recurrent disease, one of whom died. Significantly associated determinants of outcome in univariate analysis were higher age at surgery, no age-appropriate prophylactic surgery according to risk level, elevated preoperative calcitonin levels, affected codon, and the presence of lymph node metastases at surgery. On multivariate analysis only age of surgery was the single independent factor associated with persistent disease. CONCLUSIONS Prophylactic thyroidectomy beyond the recommended age is associated with persistent/recurrent disease. In addition, codon 634 mutation is associated with a high risk of recurrence requiring early surgery for all these patients.
Asunto(s)
Neoplasia Endocrina Múltiple Tipo 2a/cirugía , Tiroidectomía , Adolescente , Análisis de Varianza , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Niño , Preescolar , Codón , Femenino , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino , Neoplasia Endocrina Múltiple Tipo 2a/epidemiología , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/patología , Mutación , Estadificación de Neoplasias , Países Bajos/epidemiología , Valor Predictivo de las Pruebas , Factores de Riesgo , Estadísticas no Paramétricas , Resultado del TratamientoRESUMEN
Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant inherited cancer syndrome with the major components medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. Due to the clinical course three distinct subtypes are distinguished, MEN 2A, MEN 2B and familial medullary thyroid carcinoma. The disease is caused by germ-line mutations of the RET proto-oncogene and the localization of these mutations correlates with the onset of the development of medullary thyroid carcinoma, which is crucial for the clinical course and outcome of the disease. It therefore has a substantial influence on the clinical management of the affected patients and their relatives. This review summarizes the morphology and clinic of MEN 2-associated tumors and their respective precursor lesions.
Asunto(s)
Mutación de Línea Germinal , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasias de las Glándulas Suprarrenales/epidemiología , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/patología , Diagnóstico Diferencial , Familia , Genotipo , Enfermedad de Hirschsprung/epidemiología , Enfermedad de Hirschsprung/etiología , Enfermedad de Hirschsprung/patología , Humanos , Hipertiroidismo/epidemiología , Hipertiroidismo/etiología , Hipertiroidismo/patología , Neoplasia Endocrina Múltiple Tipo 2a/epidemiología , Neoplasia Endocrina Múltiple Tipo 2a/patología , Mutación , Feocromocitoma/epidemiología , Feocromocitoma/genética , Feocromocitoma/patología , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-ret/genética , Medición de Riesgo , Neoplasias de la Tiroides/genéticaRESUMEN
BACKGROUND: Survival of medullary thyroid carcinoma (MTC) subgroups in relation to the general population is poorly described. Data on the factors predicting long-term biochemical cure in MTC patients are nonexistent at a population level. A nationwide retrospective cohort study of MTC in Denmark from 1997 to 2014 was conducted, aiming to detect subgroups with survival similar to that of the general population and to identify prognostic factors for disease-specific survival and long-term biochemical cure. METHODS: The study included 220 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. As a representative sample of the general population, a reference population matched 50:1 to the MTC cohort was used. RESULTS: Patients diagnosed with hereditary MTC by screening (hazard ratio [HR] = 1.5 [confidence interval (CI) 0.5-4.3]), patients without regional metastases (HR = 1.4 [CI 0.9-2.3]), and patients with stage I (HR = 1.3 [CI 0.6-3.1]), stage II (HR = 1.1 [CI 0.6-2.3]), and III (HR = 1.3 [CI 0.4-4.2]) disease had an overall survival similar to the reference population. On multivariate analysis, the presence of distant metastases (HR = 12.3 [CI 6.0-25.0]) predicted worse disease-specific survival, while the absence of regional lymph node metastases (odds ratio = 40.1 [CI 12.0-133.7]) was the only independent prognostic factor for long-term biochemical cure. CONCLUSIONS: Patients with hereditary MTC diagnosed by screening, patients without regional metastases, and patients with stages I, II, and III disease may have similar survival as the general population. The presence of distant metastases predicted worse disease-specific survival, while the absence of regional metastases predicted long-term biochemical cure.
Asunto(s)
Carcinoma Medular/congénito , Neoplasia Endocrina Múltiple Tipo 2a/epidemiología , Neoplasia Endocrina Múltiple Tipo 2a/mortalidad , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/mortalidad , Adulto , Anciano , Carcinoma Medular/epidemiología , Carcinoma Medular/mortalidad , Carcinoma Medular/terapia , Bases de Datos Factuales , Dinamarca/epidemiología , Supervivencia sin Enfermedad , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 2a/terapia , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Neoplasias de la Tiroides/terapia , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: There are conflicting reports on whether familial nonmedullary thyroid cancer is more aggressive than sporadic nonmedullary thyroid cancer. Our aim was to determine if the clinical and pathologic characteristics of familial nonmedullary thyroid cancer are different than nonmedullary thyroid cancer. METHODS: We compared patients with familial nonmedullary thyroid cancer to a cohort of 53,571 nonmedullary thyroid cancer patients from the Surveillance, Epidemiology, and End Results database. RESULTS: A total of 78 patients with familial nonmedullary thyroid cancer from 31 kindreds presented at a younger age (Pâ¯=â¯.04) and had a greater rate of T1 disease (Pâ¯=â¯.019), lymph node metastasis (Pâ¯=â¯.002), and the classic variant of papillary thyroid cancer on histology (P < .001) compared with the Surveillance, Epidemiology, and End Results cohort. Patients with ≥3 affected family members presented at a younger age (Pâ¯=â¯.04), had a lesser female-to-male ratio (Pâ¯=â¯.04), and had a greater rate of lymph node metastasis (Pâ¯=â¯.009). Compared with the Surveillance, Epidemiology, and End Results cohort, we found a higher prevalence of lymph node metastasis in familial nonmedullary thyroid cancer index cases (Pâ¯=â¯.003) but not in those diagnosed by screening ultrasonography (Pâ¯=â¯.58). CONCLUSION: Patients with familial nonmedullary thyroid cancer present at a younger age and have a greater rate of lymph node metastasis. The treatment for familial nonmedullary thyroid cancer should be more aggressive in patients who present clinically and in those who have ≥3 first-degree relatives affected.
Asunto(s)
Carcinoma Medular/congénito , Neoplasia Endocrina Múltiple Tipo 2a/patología , Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/patología , Adulto , Distribución por Edad , Carcinoma Medular/epidemiología , Carcinoma Medular/patología , Carcinoma Medular/cirugía , Estudios de Cohortes , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 2a/epidemiología , Neoplasia Endocrina Múltiple Tipo 2a/cirugía , Disección del Cuello/estadística & datos numéricos , Programa de VERF , Distribución por Sexo , Cáncer Papilar Tiroideo/epidemiología , Cáncer Papilar Tiroideo/cirugía , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/cirugía , Tiroidectomía/estadística & datos numéricos , Estados Unidos/epidemiologíaRESUMEN
Background In Japan, prophylactic thyroidectomy involves out-of-pocket expense. The American Thyroid Association (ATA) recommends prophylactic thyroidectomy for medullary thyroid carcinoma (MTC) during early childhood in patients with multiple endocrine neoplasia type 2 (MEN2). The ATA reports a high frequency of postoperative complications in childhood, which also influenced the delay of prophylactic thyroidectomy in Japan. Methods This retrospective study of multiple medical centers in Japan included individuals aged <20 years diagnosed with germline RET mutations between 1997 and 2017. The onset and onset possibility were defined based on confirmed lesions or calcitonin levels. The definition of risk and prophylactic thyroidectomy were based on the ATA 2015 revised guideline. Results Twenty-one patients with MEN2 were enrolled (highest risk, n = 5; high risk, n = 5; and moderate risk, n = 11). The cumulative incidence of the onset/onset possibility reached 50% at 5 and 8 years and 100% at 9 years and 17 years in high- and moderate-risk patients, respectively. Of 7 patients with MEN2A, 71% underwent prophylactic thyroidectomy. Only one 5-year-old patient (C634Y) had increased serum calcitonin level after prophylactic thyroidectomy in the MEN2A group. The only permanent complication, which did not occur in patients who underwent total thyroidectomy alone, was hypoparathyroidism (33% of patients). This permanent complication occurred with clinically developed MTC. No permanent postoperative complications occurred in patients aged 5-6 years. Conclusions Prophylactic thyroidectomy reduces recurrence and postoperative complications in pediatric patients with MEN2. Early thyroidectomy based on only calcitonin level could possibly reduce thyroidectomy delay.
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Biomarcadores/análisis , Neoplasia Endocrina Múltiple Tipo 2a/cirugía , Recurrencia Local de Neoplasia/cirugía , Complicaciones Posoperatorias , Tiroidectomía/métodos , Adolescente , Calcitonina/metabolismo , Niño , Preescolar , Femenino , Estudios de Seguimiento , Mutación de Línea Germinal , Humanos , Japón/epidemiología , Masculino , Neoplasia Endocrina Múltiple Tipo 2a/epidemiología , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/patología , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Pronóstico , Proteínas Proto-Oncogénicas c-ret/genética , Estudios Retrospectivos , Encuestas y Cuestionarios , Factores de TiempoRESUMEN
Inherited endocrinopathies, including multiple endocrine neoplasia type 1 (MEN-1), multiple endocrine neoplasia type 2 syndromes (MEN-2A, MEN-2B, familial medullary thyroid carcinoma), and inherited syndromes with pheochromocytoma (von Hippel-Lindau disease, neurofibromatosis type 1, others), comprise a heterogeneous group of cancer susceptibility syndromes that affect one or more components of the endocrine system. During the past several years, novel findings regarding genotype-phenotype correlation have highlighted the importance of establishing a genetic diagnosis in the treatment of these diseases. Here, we present a case-based review of recent advances in the genetics, diagnosis and management of inherited endocrinopathies.
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Enfermedades del Sistema Endocrino/diagnóstico , Enfermedades del Sistema Endocrino/genética , Enfermedades del Sistema Endocrino/terapia , Carcinoma Medular/diagnóstico , Carcinoma Medular/epidemiología , Comorbilidad , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/terapia , Humanos , Modelos Biológicos , Neoplasia Endocrina Múltiple Tipo 1/diagnóstico , Neoplasia Endocrina Múltiple Tipo 1/epidemiología , Neoplasia Endocrina Múltiple Tipo 1/genética , Neoplasia Endocrina Múltiple Tipo 2a/diagnóstico , Neoplasia Endocrina Múltiple Tipo 2a/epidemiología , Neoplasia Endocrina Múltiple Tipo 2a/genética , Paraganglioma/diagnóstico , Paraganglioma/epidemiología , Paraganglioma/etiología , Feocromocitoma/diagnóstico , Feocromocitoma/epidemiología , Feocromocitoma/etiología , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/epidemiologíaRESUMEN
Multiple endocrine neoplasia type 1 is a rare genetic syndrome, characterized by the co-occurrence, in the same individual or in related individuals of the same family, of hyperparathyroidism, duodenopancraetic neuroendocrine tumors, pituitary adenomas, adrenocortical tumors, and neuroendocrine tumors (carcinoids) in the thymus, the bronchi, or the stomach. Multiple endocrine neoplastic type 2 is a rare genetic syndrome, characterized by the familial occurrence of medullary thyroid carcinoma either isolated or associated with pheochromocytoma, primary hyperparathyroidism, or typical features (Marfanoid habitus, mucosal neuromas). Subjects with clinical MEN1 and those who carry a mutation in the MEN1 gene should be offered biochemical and imaging screening in order to detect tumors and evaluate their progression over time. Children with mutation in the RET gene should have prophylactic total thyroidectomy according to the category of aggressiveness of the detected mutation whereas those with clinical MEN2 should be operated on upon diagnosis. In MEN1 patients, special attention should be paid to evaluate the progression duodenopancraetic neuroendocrine tumors because of their malignant potential. Also, thymic neuroendocrine tumors should be detected as soon as possible because they represent the most lethal tumor. In MEN2, calcitonin and carcinoembryonic antigen (CEA) serve as excellent tumor markers for medullary thyroid carcinoma. Their preoperative levels are correlated with tumor size and predict postoperative cure. Moreover, calcitonin or CEA doubling time has important prognostic value. In both MEN syndromes, multidisciplinary approaches are very important in the care of affected patients. Moreover, those patients should be comprehensively informed and enabled to participate in the decision-making procedure. In addition to multidisciplinary approaches, every effort should be made to follow the recommendations and guidelines issued by national (the French Group of Endocrine Tumors) and international groups.
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Neoplasia Endocrina Múltiple Tipo 1 , Neoplasia Endocrina Múltiple Tipo 2a , Humanos , Neoplasia Endocrina Múltiple Tipo 1/diagnóstico , Neoplasia Endocrina Múltiple Tipo 1/epidemiología , Neoplasia Endocrina Múltiple Tipo 1/genética , Neoplasia Endocrina Múltiple Tipo 1/terapia , Neoplasia Endocrina Múltiple Tipo 2a/diagnóstico , Neoplasia Endocrina Múltiple Tipo 2a/epidemiología , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/terapia , Mutación , PronósticoRESUMEN
Over the last years, the knowledge of MEN2 and non-MEN2 familial forms of pheochromocytoma (PHEO) has increased. In MEN2, PHEO is the second most frequent disease: the penetrance and age at diagnosis depend on the mutation of RET Given the prevalence of bilateral PHEO (50% by age 50), adrenal sparing surgery, aimed at sparing a part of the adrenal cortex to avoid adrenal insufficiency, should be systematically considered in patients with bilateral PHEO. Non-MEN2 familial forms of PHEO now include more than 20 genes: however, only small phenotypic series have been reported, suggesting that phenotypic features of isolated hereditary PHEO must be better explored, and follow-up series are needed to better understand the outcome of patients carrying mutations of these genes. The first part of this review will mainly focus on these points. In the second part, a focus will be given on MEN2 and non-MEN2 familial forms of hyperparathyroidism (HPTH). Again, the management of MEN2 HPTH should be aimed at curing the disease while preserving an optimal quality of life by a tailored parathyroidectomy. The phenotypes and outcome of MEN1-, MEN4- and HRPT2-related HPTH are briefly described, with a focus on the most recent literature data and is compared with familial hypocalciuric hypercalcemia.
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Neoplasias de las Glándulas Suprarrenales , Hiperparatiroidismo , Neoplasia Endocrina Múltiple Tipo 2a , Feocromocitoma , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/epidemiología , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/terapia , Humanos , Hiperparatiroidismo/diagnóstico , Hiperparatiroidismo/epidemiología , Hiperparatiroidismo/genética , Hiperparatiroidismo/terapia , Neoplasia Endocrina Múltiple Tipo 2a/diagnóstico , Neoplasia Endocrina Múltiple Tipo 2a/epidemiología , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/terapia , Feocromocitoma/diagnóstico , Feocromocitoma/epidemiología , Feocromocitoma/genética , Feocromocitoma/terapiaRESUMEN
BACKGROUND: Hereditary medullary thyroid carcinoma can present as a part of multiple endocrine neoplasia syndrome by rearranged during transfection gene mutation. We evaluated the prevalence of rearranged during transfection gene mutation in patients who have medullary thyroid carcinoma and the correlations of genotype with medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism according to the revised American Thyroid Association risk level. METHODS: A total of 331 patients were diagnosed with medullary thyroid carcinoma, 172 of whom were tested for the rearranged during transfection germline mutation by sequencing of exon 8, 10, 11, and 13-16. These patients were diagnosed during the years 1982-2012 at 2 Korean tertiary hospitals. Patients were analyzed according to the route of diagnosis (screened versus index cases) or the mutational site of rearranged during transfection gene (the American Thyroid Association risk group). RESULTS: Rearranged during transfection mutation was found in 23.8% of patients tested, showing a decreasing trend with time. The most commonly mutated codon was codon 634 (37.1%), followed by codon 918 (14.3%). rearranged during transfection-positive patients were younger than rearranged during transfection-negative patients, although no other clinicopathologic characteristics differed. Screened cases were younger and had smaller tumors than index cases. Among rearranged during transfection-positive patients, pheochromocytoma manifested in 35.1% and hyperparathyroidism in 7.0%. Notably, pheochromocytoma and hyperparathyroidism emerged at any time after the diagnosis of medullary thyroid carcinoma. The American Thyroid Association risk-group analysis demonstrated that medullary thyroid carcinoma patients in the highest risk group were younger, had larger tumors, and higher disease-specific mortality. Similar results for pheochromocytoma were found, according to the American Thyroid Association risk group, although the results were not significant. CONCLUSIONS: Korean patients who have medullary thyroid carcinoma showed a similar distribution of rearranged during transfection gene mutation with those in Western countries. The American Thyroid Association risk classification was shown to be useful for pheochromocytoma, as well as for medullary thyroid carcinoma. Familial screening for rearranged during transfection mutation and lifelong monitoring for associated pheochromocytoma should be emphasized in hereditary medullary thyroid carcinoma.
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Carcinoma Medular/congénito , Neoplasia Endocrina Múltiple Tipo 2a/genética , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias de la Tiroides/genética , Adolescente , Adulto , Carcinoma Medular/epidemiología , Carcinoma Medular/genética , Carcinoma Medular/patología , Niño , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 2a/epidemiología , Neoplasia Endocrina Múltiple Tipo 2a/patología , Mutación , Fenotipo , República de Corea/epidemiología , Glándula Tiroides/patología , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/patología , Adulto JovenRESUMEN
Multiple endocrine neoplasia type 2 (MEN2) is an hereditary disease with a prevalence of 1/5000. Three phenotypic variants have been identified: MEN2A associates medullary thyroid carcinoma (MTC) to pheochromocytoma in about 20-50% of cases and to primary hyperparathyroidism in 5-20% of cases; MEN2B associates MTC to pheochromocytoma in 50% of cases, to marphanoid habitus and to mucosal and digestive ganglioneuromatosis whereas in familial isolated medullary thyroid carcinoma (FMTC), the other components of the disease are absent. In MEN2, natural history of the disease and a common embryologic origin (neural crest) may explain the phenotypes observed in the organ involved, beginning from the stage of hyperplasia to adenoma and cancer. MEN2 is an inherited autosomal dominant disease with a complete penetrance, related to germline mutation in the proto-oncogene RET. MTC represent the most frequent circumstance of diagnosis. Pheochromocytoma and HPT may reveal the disease unfrequently and are systematically associated to undiagnosed MTC which is present yet. Analysis of the RET gene allows to confirm the diagnosis of MEN2 by identifying the causal germline mutation. Management of MEN2 patients include thyroidectomy associated to cervical central and bilateral lymph nodes dissection for MTC, unilateral adrenalectomy for unilateral pheochromocytoma or bilateral adrenalectomy when both glands are involved, and selective resection of pathologic parathyroid glands for HPT. Familial genetic screening detects at risk subjects who will develop the disease and allows to manage them at the earliest stage of the disease by perform early or prophylactic thyroidectomy such giving them the best chance of cure. Prognosis of MEN2 is mainly related to the stage-dependant prognosis of MTC, thus pointing the necessity of a complete thyroid surgery for index cases with MTC and the earliest thyroidectomy for screened at risk subjects.