RESUMO
Objective: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized by its clinical variability and complexity in diagnosis and treatment. We performed both clinical and molecular descriptions of four families with MEN1 in a follow-up at a tertiary center in Brasília. Methods: From a preliminary review of approximately 500 medical records of patients with pituitary neuroendocrine tumor (PitNET) from the database of the Neuroendocrinology Outpatient Clinic of the University Hospital of Brasília, a total of 135 patients met the criteria of at least two affected family members. From this cohort, we have identified 34 families: only four with a phenotype of MEN1 and the other 30 families with the phenotype of familial isolated pituitary adenoma (FIPA). Eleven patients with a clinical diagnosis of MEN1 from these four families were selected. Results: Variants in MEN1 gene were identified in all families. One individual from each family underwent genetic testing using targeted high-throughput sequencing (HTS). All patients had primary hyperparathyroidism (PHPT), and the second most common manifestation was PitNET. One individual had well-differentiated liposarcoma, which has been previously reported in a single case of MEN1. Three variants previously described in the database and a novel variant in exon 2 have been found. Conclusions: The study allowed the genotypic and phenotypic characterization of families with MEN1 in a follow-up at a tertiary center in Brasília.
Assuntos
Adenoma Hipofisário Secretor de Hormônio do Crescimento , Neoplasia Endócrina Múltipla Tipo 1 , Tumores Neuroendócrinos , Neoplasias Hipofisárias , Humanos , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/patologia , Brasil/epidemiologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologiaRESUMO
BACKGROUND/AIM: Familial multiple endocrine neoplasia type 1 (MEN1) is a rare disorder mostly associated with germline MEN1 mutations. MATERIALS AND METHODS: Genotyping of the MEN1, cyclin-dependent kinase inhibitor 1B (CDKN1B) and aryl hydrocarbon receptor-interacting protein (AIP) genes using Sanger sequencing was carried out in a family with MEN1 and the resulting germline variants genotyped in an additional 95 ethnically matched controls. RESULTS: A missense variant in AIP (p.Arg16His) gene and a truncating mutation (p.Gly111fs*8) in MEN1 gene were both detected in the proband and his father, showing limited co-segregation with phenotype. p.Arg16His AIP missense variant was detected in one control. CONCLUSION: There are conflicting data regarding the functional effects of AIP p.Arg16His and its role in disease development. We demonstrated the co-occurrence of p.Arg16His AIP missense variant in a patient with a bona fide MEN1 mutation. Our finding of p.Arg16His AIP in one of the 95 controls and its co-occurrence with MEN1 in a patient suggests that it is more likely that this variant is a rare polymorphism, unrelated to MEN1 pathogenesis.
Assuntos
Mutação em Linhagem Germinativa , Peptídeos e Proteínas de Sinalização Intracelular/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Adulto , Saúde da Família , Feminino , Humanos , Masculino , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/patologia , Linhagem , FenótipoRESUMO
Preimplantation genetic diagnosis was carried out for embryonic analysis in a patient with multiple endocrine neoplasia type 1 (MEN1). This is a rare autosomal-dominant cancer syndrome and the patients with MEN1 are characterized by the occurrence of tumors in multiple endocrine tissues, associated with germline and somatic inactivating mutations in the MEN1 gene. This case report documents a successful preimplantation genetic diagnosis (PGD) involving a couple at-risk for MEN1 syndrome, with a birth of a healthy infant. The couple underwent a cycle of controlled ovarian stimulation and intracytoplasmic sperm injection (ICSI). Embryos were biopsied at the blastocyst stage and cryopreserved; we used PCR-based DNA analysis for PGD testing. Only one of the five embryos analyzed for MEN1 syndrome was unaffected. This embryo was thawed and transferred following endometrial preparation. After positive ßHCG test; clinical pregnancy was confirmed by ultrasound, and a healthy infant was born. PGD for single gene disorders has been an emerging therapeutic tool for couples who are at risk of passing a genetic disease on to their offspring.
Assuntos
Blastocisto/patologia , Neoplasia Endócrina Múltipla Tipo 1 , Diagnóstico Pré-Implantação/métodos , Adulto , Biópsia , Feminino , Fertilização in vitro , Testes Genéticos/métodos , Humanos , Masculino , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/patologia , Linhagem , Gravidez , Injeções de Esperma IntracitoplásmicasRESUMO
BACKGROUND: The most common manifestation of MEN 1 syndrome is primary hyperparathyroidism (PHPT) with parathyroid multiglandular affectation. The intrathyroidal situation represents 3-4% of all glands, and it is the second most frequent location in the cervical ectopias. CLINICAL CASE: 11 year old patient, with a family history of MEN1 syndrome and carrier of this same mutation. Patient presents HPTP with osteopenia. The cervical ultrasound shows three compatible images with pathological parathyroid glands (bilateral lower and upper left). The Scan and MRI are normal. Bone densitometry displays data on osteopenia. The patient is surgically intervened, only the upper parathyroid glands are located and removed, after this implantation is performed on the forearm, to prevent the possible devascularization in the dissection of the other glands. However, osteopenia persists and an elevated PTH, therefore new diagnostic tests are held which seem to show two lower parathyroid glands with intrathyroidal location. The patient is reoperated. A subtotal parathyroidectomy of the lower right gland and the resection of the left gland is performed, with the use of intraoperative ultrasound and placement of harpoon. The intraoperative pathology study confirms parathyroid tissue in both cases. DISCUSSION: It is necessary to locate the parathyroid glands preoperatively in order to alert us of the existence of topographical and ectopia abnormalities, as well as their intrathyroidal location (0.5-3.6%). CONCLUSION: The intraoperative ultrasound can be a complement to the experience of the endocrine surgeon for the localization of the parathyroid glands and therefore can help determine the best surgical strategy for each clinical case.
Assuntos
Coristoma/etiologia , Neoplasia Endócrina Múltipla Tipo 1/complicações , Glândulas Paratireoides , Doenças da Glândula Tireoide/etiologia , Doenças Ósseas Metabólicas/etiologia , Criança , Coristoma/diagnóstico por imagem , Coristoma/cirurgia , Feminino , Antebraço , Humanos , Hiperparatireoidismo Primário/etiologia , Neoplasia Endócrina Múltipla Tipo 1/patologia , Glândulas Paratireoides/diagnóstico por imagem , Glândulas Paratireoides/cirurgia , Glândulas Paratireoides/transplante , Paratireoidectomia/métodos , Doenças da Glândula Tireoide/diagnóstico por imagem , Doenças da Glândula Tireoide/cirurgia , Ultrassonografia de IntervençãoRESUMO
OBJECTIVE: To evaluate frequency, anatomic presentation, and quantities of supernumerary parathyroids glands in patients with primary hyperparathyroidism (HPT1) associated with multiple endocrine neoplasia type 1 (MEN1), as well as the importance of thymectomy, and the benefits of localizing examinations for those glands. METHODS: Forty-one patients with hyperparathyroidism associated with MEN1 who underwent parathyroidectomy between 1997 and 2007 were retrospectively studied. The location and number of supernumerary parathyroids were reviewed, as well as whether cervical ultrasound and parathyroid SESTAMIBI scan (MIBI) were useful diagnostic tools. RESULTS: In five patients (12.2%) a supernumerary gland was identified. In three of these cases (40%), the glands were near the thyroid gland and were found during the procedure. None of the imaging examinations were able to detect supernumerary parathyroids. In one case, only the pathologic examination could find a microscopic fifth gland in the thymus. In the last case, the supernumerary gland was resected through a sternotomy after a recurrence of hyperparathyroidism, ten years after the initial four-gland parathyroidectomy without thymectomy. MIBI was capable of detecting this gland, but only in the recurrent setting. Cervical ultrasound did not detect any supernumerary glands. CONCLUSION: The frequency of supernumerary parathyroid gland in the HPT1/MEN1 patients studied (12.2%) was significant. Surgeons should be aware of the need to search for supernumerary glands during neck exploration, besides the thymus. Imaging examinations were not useful in the pre-surgical location of these glands, and one case presented a recurrence of hyperparathyroidism.
Assuntos
Hiperparatireoidismo/patologia , Neoplasia Endócrina Múltipla Tipo 1/patologia , Glândulas Paratireoides/anormalidades , Adulto , Idoso , Feminino , Humanos , Hiperparatireoidismo/etiologia , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 1/complicações , Glândulas Paratireoides/patologia , Glândulas Paratireoides/cirurgia , Estudos Retrospectivos , Timectomia , Adulto JovemRESUMO
OBJECTIVE: To evaluate frequency, anatomic presentation, and quantities of supernumerary parathyroids glands in patients with primary hyperparathyroidism (HPT1) associated with multiple endocrine neoplasia type 1 (MEN1), as well as the importance of thymectomy, and the benefits of localizing examinations for those glands. METHODS: Forty-one patients with hyperparathyroidism associated with MEN1 who underwent parathyroidectomy between 1997 and 2007 were retrospectively studied. The location and number of supernumerary parathyroids were reviewed, as well as whether cervical ultrasound and parathyroid SESTAMIBI scan (MIBI) were useful diagnostic tools. RESULTS: In five patients (12.2%) a supernumerary gland was identified. In three of these cases (40%), the glands were near the thyroid gland and were found during the procedure. None of the imaging examinations were able to detect supernumerary parathyroids. In one case, only the pathologic examination could find a microscopic fifth gland in the thymus. In the last case, the supernumerary gland was resected through a sternotomy after a recurrence of hyperparathyroidism, ten years after the initial four-gland parathyroidectomy without thymectomy. MIBI was capable of detecting this gland, but only in the recurrent setting. Cervical ultrasound did not detect any supernumerary glands. CONCLUSION: The frequency of supernumerary parathyroid gland in the HPT1/MEN1 patients studied (12.2%) was significant. Surgeons should be aware of the need to search for supernumerary glands during neck exploration, besides the thymus. Imaging examinations were not useful in the pre-surgical location of these glands, and one case presented a recurrence of hyperparathyroidism.
OBJETIVO: Avaliação da frequência, da localização anatômica e do número de paratireoides extranumerárias em pacientes com hiperparatireoidismo primário (HPT1) associado a neoplasia endócrina múltipla tipo 1(NEM1), além da avaliação da importância da timectomia e da utilidade dos exames radiológicos para localização destes. MÉTODOS: Foram avaliados de forma retrospectiva 41 pacientes portadores de NEM1 com HPT1 submetidos a paratireoidectomia entre 1997 e 2007. O número de glândulas supranumerárias encontradas e a sua localização foram revisados, assim como a utilidade do ultrassom cervical e do SESTAMIBI (MIBI) de paratireoide como ferramentas diagnósticas. RESULTADOS: Em cinco pacientes (12,2%) foram identificadas glândulas supranumerárias. Em três destes (40%), as glândulas estavam próximas à glândula tireoide e foram encontradas durante a exploração cirúrgica. Os exames de imagem não foram úteis para a localização destas glândulas. Em um caso, apenas o exame anatomopatológico foi capaz de encontrar uma glândula extranumerária microscópica localizada no timo. No último caso, uma quinta glândula foi ressecada por meio de esternotomia após a recidiva do hiperparatireoidismo, cerca de 10 anos após a paratireoidectomia realizada sem timectomia na ocasião. Neste caso o MIBI detectou esta paratireoide apenas após a recidiva da doença. Em nenhum dos casos o ultrassom cervical foi capaz de detectar glândulas extranumerárias. CONCLUSÃO: A frequência de paratireoides supranumerárias em nossa casuística foi significativa (12,2%). Durante a exploração cervical, o cirurgião deve estar atento para localizar glândulas extranumerárias além do timo. Exames de imagem não foram úteis na localização préoperatória dessas glândulas, e em um caso houve recidiva do hiperparatireoidismo.
Assuntos
Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Hiperparatireoidismo/patologia , Neoplasia Endócrina Múltipla Tipo 1/patologia , Glândulas Paratireoides/anormalidades , Hiperparatireoidismo/etiologia , Neoplasia Endócrina Múltipla Tipo 1/complicações , Glândulas Paratireoides/patologia , Glândulas Paratireoides/cirurgia , Estudos Retrospectivos , TimectomiaRESUMO
We briefly review the characteristics of pituitary tumors associated with multiple endocrine neoplasia type 1. Multiple endocrine neoplasia type 1 is an autosomal-dominant disorder most commonly characterized by tumors of the pituitary, parathyroid, endocrine-gastrointestinal tract, and pancreas. A MEDLINE search for all available publications regarding multiple endocrine neoplasia type 1 and pituitary adenomas was undertaken. The prevalence of pituitary tumors in multiple endocrine neoplasia type 1 may vary from 10% to 60% depending on the studied series, and such tumors may occur as the first clinical manifestation of multiple endocrine neoplasia type 1 in 25% of sporadic and 10% of familial cases. Patients were younger and the time between initial and subsequent multiple endocrine neoplasia type 1 endocrine lesions was significantly longer when pituitary disease was the initial manifestation of multiple endocrine neoplasia type 1. Tumors were larger and more invasive and clinical manifestations related to the size of the pituitary adenoma were significantly more frequent in patients with multiple endocrine neoplasia type 1 than in subjects with non-multiple endocrine neoplasia type 1. Normalization of pituitary hypersecretion was much less frequent in patients with multiple endocrine neoplasia type 1 than in subjects with non-multiple endocrine neoplasia type 1. Pituitary tumors in patients with multiple endocrine neoplasia type 1 syndrome tend to be larger, invasive and more symptomatic, and they tend to occur in younger patients when they are the initial presentation of multiple endocrine neoplasia type 1.
Assuntos
Adenoma/genética , Neoplasia Endócrina Múltipla Tipo 1/genética , Mutação , Neoplasias Hipofisárias/genética , Adenoma/patologia , Genes Neoplásicos/genética , Mutação em Linhagem Germinativa/genética , Humanos , Neoplasia Endócrina Múltipla Tipo 1/patologia , Neoplasias Hipofisárias/patologia , SíndromeRESUMO
We briefly review the characteristics of pituitary tumors associated with multiple endocrine neoplasia type 1. Multiple endocrine neoplasia type 1 is an autosomal-dominant disorder most commonly characterized by tumors of the pituitary, parathyroid, endocrine-gastrointestinal tract, and pancreas. A MEDLINE search for all available publications regarding multiple endocrine neoplasia type 1 and pituitary adenomas was undertaken. The prevalence of pituitary tumors in multiple endocrine neoplasia type 1 may vary from 10% to 60% depending on the studied series, and such tumors may occur as the first clinical manifestation of multiple endocrine neoplasia type 1 in 25% of sporadic and 10% of familial cases. Patients were younger and the time between initial and subsequent multiple endocrine neoplasia type 1 endocrine lesions was significantly longer when pituitary disease was the initial manifestation of multiple endocrine neoplasia type 1. Tumors were larger and more invasive and clinical manifestations related to the size of the pituitary adenoma were significantly more frequent in patients with multiple endocrine neoplasia type 1 than in subjects with non-multiple endocrine neoplasia type 1. Normalization of pituitary hypersecretion was much less frequent in patients with multiple endocrine neoplasia type 1 than in subjects with non-multiple endocrine neoplasia type 1. Pituitary tumors in patients with multiple endocrine neoplasia type 1 syndrome tend to be larger, invasive and more symptomatic, and they tend to occur in younger patients when they are the initial presentation of multiple endocrine neoplasia type 1.
Assuntos
Humanos , Adenoma/genética , Mutação , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasias Hipofisárias/genética , Adenoma/patologia , Genes Neoplásicos/genética , Mutação em Linhagem Germinativa/genética , Neoplasia Endócrina Múltipla Tipo 1/patologia , Neoplasias Hipofisárias/patologia , SíndromeRESUMO
Differences in bone mineral density (BMD) patterns have been recently reported between multiple endocrine neoplasia type 1-related primary hyperparathyroidism (HPT/MEN1) and sporadic primary HPT. However, studies on the early and later outcomes of bone/renal complications in HPT/MEN1 are lacking. In this cross-sectional study, performed in a tertiary academic hospital, 36 patients cases with uncontrolled HPT from 8 unrelated MEN1 families underwent dual-energy X-ray absorptiometry (DXA) scanning of the proximal one-third of the distal radius (1/3DR), femoral neck, total hip, and lumbar spine (LS). The mean age of the patients was 38.9 ± 14.5 years. Parathyroid hormone (PTH)/calcium values were mildly elevated despite an overall high percentage of bone demineralization (77.8%). In the younger group (<50 years of age), demineralization in the 1/3DR was more frequent, more severe, and occurred earlier (40%; Z-score -1.81 ± 0.26). The older group (>50 years of age) had a higher frequency of bone demineralization at all sites (p < .005) and a larger number of affected bone sites (p < .0001), and BMD was more severely compromised in the 1/3DR (p = .007) and LS (p = .002). BMD values were lower in symptomatic (88.9%) than in asymptomatic HPT patients (p < .006). Patients with long-standing HPT (>10 years) and gastrinoma/HPT presented significantly lower 1/3DR BMD values. Urolithiasis occurred earlier (<30 years) and more frequently (75%) and was associated with related renal comorbidities (50%) and renal insufficiency in the older group (33%). Bone mineral- and urolithiasis-related renal complications in HPT/MEN1 are early-onset, frequent, extensive, severe, and progressive. These data should be considered in the individualized clinical/surgical management of patients with MEN1-associated HPT.