Multiple Endocrine Neoplasia 2A Syndrome Research Articles

Bilateral Posterior Retroperitoneoscopic Adrenalectomy with Cortical Sparing on Right Side

Cortical sparing adrenalectomy allows for resection of adrenal tumor(s) while preserving unaffected adrenal tissue to prevent adrenal insufficiency. This is especially important in patients affected with bilateral adrenal tumors, typically pheochromocytomas. Posterior retroperitoneoscopic adrenalectomy (PRA) allows for a minimally invasive approach to adrenal gland resection compared to the more traditional laparoscopic transabdominal adrenalectomy and open approaches. The PRA technique is increasingly used by high-volume endocrine surgeons throughout the world. This approach is ideal to address patients with bilateral disease and was utilized in this case of a patient presenting with bilateral pheochromocytomas in the setting of multiple endocrine neoplasia 2A syndrome.

Multiple Endocrine Neoplasia Type 2A Patient with Metastatic Medullary Thyroid Carcinoma and Unilateral Multicentric Pheochromocytoma: A Case Report and Literature Review

Introduction: Multiple endocrine neoplasia 2A (MEN2A) is an autosomal dominant syndrome associated with germline mutations in the RET proto-oncogene that may lead to medullary thyroid carcinomas (MTC), pheochromocytomas, and parathyroid adenomas. Patients generally present between the ages of 20 and 30 years. MEN2 patients are stratified for risk based upon the RET mutation, and a genotype-phenotype correlation exists. Case Report: We describe a 36-year-old male recently diagnosed with MEN2A syndrome and RET oncogene mutation [c.1900T>C;p.Cys634Arg], which is a high risk category. He had elevated calcitonin, calcium, parathyroid hormone, and alkaline phosphatase levels with decreased ionized calcium. 24-hour urine testing showed elevated metanephrines and catecholamines. Imaging studies showed a right adrenal mass and multicentric thyroid nodules with a mass adherent to the right inferior posterior thyroid lobe. Right adrenalectomy histologic evaluation revealed multicentric pheochromocytomas in the right adrenal gland. Total thyroidectomy with bilateral central and lateral neck dissections confirmed multicentric MTC metastatic to one right lateral neck lymph node. Although only one parathyroid gland was removed, the findings were suggestive of parathyroid adenoma. Discussion and Conclusion: This case is remarkable for the relatively advanced patient age for presentation with this syndrome given the high-risk category as well as multifocality of the associated neoplasms. The general pathologist should be aware of the MEN2 risk stratification categories based on molecular profiling and the implications on patient care.

Syncronous medullar thyroid cancer and primary hyperparathyroidism on a female within the sixth decade of life with positive family history for type 2A MEN syndrome

Medullar thyroid cancer (MTC) may be sporadic or familial, either linked with pheocromocytoma (PHEO) and primary hyperparathyrodism (PHP), as seen in type 2A MEN (Multiple Endocrine Neoplasia) syndrome, either isolated. This is a 56-year old female known with mild arterial hypertension controlled under therapy, having a daughter with type 2A MEN syndrome (PHEO, MTC, PHP). Mild hypercalcemia and high parathormone were consistent for PHP, while calcitonin was 20 times above the upper normal limit for MTC. The PHEO tests were negative. Anterior cervical ultrasound confirmed a 2.7 cm thyroid nodule, local lymph nodes, and enlargement of inferior and superior left prarathyroids. After total thyroidectomy with bilateral neck dissection and excision of the left inferior and superior parathyroid glands, MTC and parathyroid hyperplasia was confirmed. Calcitonin decreased to 5 times above the normal level. Further close follow-up and therapy of residual MTC is needed. MEN 2A Syndrome may embrace various clinical presentations with more or less aggressive tumours, sometimes allowing a long time survival without neoplasia confirmation or incomplete phenotype until advanced age.

RET gene mutations spectrum in patients with medullary thyroid carcinoma (MTC) from Great Poland region

Medullary thyroid carcinoma (MTC) is an epithelial tumor of the thyroid gland, derived from thyroid parafollicular C cells and represents approximately 4% of thyroid carcinomas. In 50 % of patients, MTC is diagnosed at an advanced stage. Due to a lack of TSH receptors on C-cells surface MTC does not respond to suppression therapy with TSH and radio-iodine treatment, and thereby it conferring worse outcomes overall. 5-year survival rates range from 75% for patients with stage III disease to 40% for patients with stage IV disease. MTC is associated with one of three clinically different, inherited endocrine syndromes caused by germline mutations in the RET gene. It encodes a transmembrane receptor tyrosine kinase which is expressed in cells derived from the neural crest. Activating mutations in the RET gene are detected in the majority (95%) patients with an inherited medullary thyroid carcinoma and approximately 30-50% of cases without family history. Familial medullary thyroid carcinomas (FMTCs) are associated with mutations in codons 609, 611, 618, and 620 (exon 10), as well as codon 768 (exon 13) and codon 804 (exon 14). In FMTC patients, MTC is often the only clinical symptom. Multiple endocrine neoplasia (MEN) 2A is associated in the most cases, with RET gene mutations in codons 609, 611, 618, and 620, as well as in codon 634. Patients with MEN2A typically have MTC, pheochromocytoma, and primary hyperparathyroidism (PHPT). Patients diagnosed with MEN 2B present the most aggressive type of MTC, pheochromocytoma but not PHPT, musculoskeletal abnormalities and other developmental defects. This syndrome is associated mostly with mutation in codon 918 in exon 16. Here we report the RET gene mutations spectrum in a group from Great Poland (Wielkopolska) region. Molecular analysis was performed for 304 individuals: patients with diagnosed MTC or apparent MEN 2A syndrome and first and second degree relatives. Studied group included also one family with MEN 2B syndrome. All patients were diagnosed in the Department of Endocrinology, Metabolism, and Internal Diseases of the Poznan University of Medical Sciences. We screened RET gene exons: 10, 11, 13-16 using pyrosequencing for specific codons and HRMA technique followed by Sanger sequencing. Identification of RET gene mutations was possible for 50 patients (32%). This group included 12 family cases and in 6 subjected individuals diagnosis were possible before cancer occurring. In a group of 106 (68%) MTC patients we did not detect mutations in analyzed RET gene regions. The most frequent was missense substitutions occurring in codon 634 (72%): C634R (58%), C634G (10%) and C634Y (4%). Surprisingly, in our group of patients we did not detect mutations in exon 10, as they are frequent in other populations. However, we observed 3 different mutations in exon 13 (18%) and in exon 14 (6%). In four unrelated patients with negative family history we detected missense change Y791F, which is associated with late onset MTC, but interestingly one of patients was homozygous and presented more aggressive course of the disease (characterized with multifocality and onset in the moment of diagnosis at 47 years of age). In MEN 2B family, M918A mutation was detected. Due to the fact, that we observe a different mutational spectrum in our patients, we consider more extensive analysis of the RET gene as reasonable.

Multiple endocrine neoplasia-2A-revisited

Multiple endocrine neoplasia-2A (MEN-2A) is a rare syndrome. MEN-2 is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism. MTC is the most consistent feature in all subtypes of MEN-2. In MEN-2A, approximately 70–95% of individuals develop MTC, 50% develop pheochromocytoma, and 15–30% develop hyperparathyroidism. Identification of a germline REarranged in transfection mutation or the identification of the clinical features of MEN-2A in other first-degree relatives is required to make the diagnosis, in those patients with only one or two clinical features. We present the case of a family with MEN-2A syndrome. Here, the patient was first operated for MTC and following further investigation was detected to have pheochromocytoma. In her family history, she had a daughter who was earlier operated for MTC. After 5 years of follow-up, she is doing well. This is an additional case of MEN-2A.

RET codon 618 mutations in Saudi families with multiple endocrine neoplasia Type 2A and familial medullary thyroid carcinoma.

BACKGROUND AND OBJECTIVESCertain diseases such as multiple endocrine neoplasia (MEN) 2A, MEN 2B, familial and sporadic medullary thyroid carcinoma (MTC) and renal dysgenesis are related to abnormalities of the RET protein. Our aim was to evaluate the frequency of RET mutation in 10 Saudi families with MEN type 2A and familial MTC.DESIGN AND SETTINGA cross-sectional prospective study of patients followed up at King Abdulaziz University Hospital and King Abdulaziz Medical City, Jeddah, between March 2001 and March 2011.PATIENTS AND METHODSGenomic DNA was isolated from peripheral blood leukocytes of all subjects by standard procedures. Exons 10, 11, 13, 14 and 16 of the RET proto-oncogene were analyzed by single-strand conformation polymorphism, direct DNA sequencing and/or restriction enzyme analysis.RESULTSWe screened 79 subjects for the RET mutation. Of which 43 subjects had hereditary MTC were enrolled in this study. MEN type 2A was identified in 25 subjects; MTC was diagnosed in all 25 subjects (100%), pheochromocytoma in 13 subjects (52%) and hyperparathyroidism in 4 subjects (16%). The most frequent genotype in patients with MEN 2A syndrome was a codon 618 mutation (46.6%), followed by a codon 634 mutation (44.2%). Among the 5 families with MEN 2A, 3 had a mutation at codon 634, whereas 2 had a mutation at codon 618.CONCLUSIONThe most frequent RET proto-oncogene mutation in our series was in codon 618 (exon 10).

A case of Takotsubo’s cardiomyopathy and multiple endocrine neoplasia 2A syndrome

A case of Takotsubo’s cardiomyopathy and multiple endocrine neoplasia 2A syndrome

Medullary thyroid carcinoma identified within the first year of life in children with hereditary multiple endocrine neoplasia type 2A (codon 634) and 2B

Early prophylactic thyroidectomy in patients with multiple endocrine neoplasia (MEN) type 2 offers the best chance for a normal life expectancy. To analyze the results of thyroidectomy performed during the first year of life in six patients with MEN 2A (codon 634) or MEN 2B (codon 918) syndrome. A university hospital-based prospective study from 2001 to 2008. Six family members affected either by MEN 2A (n=3) or MEN 2B (n=3) syndrome were identified through neonatal genetic screening. Total thyroidectomy was performed at a median age of 0.8 year in the six patients, with central lymph node dissection in five. Bilateral millimetric medullary thyroid carcinoma (MTC) was found in all patients, with a unilateral lymph node micrometastasis in two of the three MEN 2B patients. Before thyroidectomy, MEN 2B patients had much higher basal serum calcitonin levels than those with MEN 2A and controls. After thyroidectomy, with a median follow-up of 3.3 years, the six patients had no evidence of persistent MTC. Bilateral millimetric MTC may be present during the first year of life in these patients, with lymph node metastases also occurring in MEN 2B patients. These results support a total thyroidectomy at the age of about one year in MEN 2A (codon 634) children with an abnormal serum calcitonin level, and a total thyroidectomy with central neck dissection within the first weeks of life in MEN 2B patients.

First Description of Parathyroid Disease in Multiple Endocrine Neoplasia 2A Syndrome

Hyperparathyroidism and/or parathyroid hyperplasia, medullary thyroid carcinoma (MTC), and pheochromocytomas compose the hallmarks of the multiple endocrine neoplasia type 2A (MEN 2A) syndrome. Revisiting a report in 1939 of a patient with hyperparathyroidism and parathyroid hyperplasia led to a search for evidence of MEN 2A. From medical records and discussion with family members, longitudinal follow-up of the patient and her descendants was obtained. Molecular diagnostics were integrated in the care of subsequent generations. The literature on hyperparathyroidism and MEN 2A was reviewed. Children of the proband exhibited all components of MEN 2A and the RET mutation of 634 TGC>CGC. The pedigree was typical for this mutation. Papers on anthropologic studies demonstrate skeletal evidence of hyperparathyroidism in humans centuries ago. The initial report of the proband preceded the publications defining both MTC and MEN 2A. The values of in-depth family histories and genetic analyses are exemplified.

Severe reversible dilated cardiomyopathy in a patient with multiple endocrine neoplasia 2A syndrome

Pheochromocytoma may infrequently lead to dilated cardiomyopathy, which may reverse partially or completely after treatment. Progressive dyspnea, palpitations, and paroxysmal attacks of severe hypertension leading to cardiac failure had developed in a 25-yr-old woman. Chest radiography and echocardiography revealed a massive 4-chamber dilatation of the heart with an ejection fraction of 12%. Twenty-four-h urinary vanillylmandelic acid and metanephrine levels were elevated. Magnetic resonance imaging detected a large mass lesion in the right adrenal gland. Oral glucose tolerance testing revealed diabetes mellitus. Medical drug therapy with alpha-blocker, angiotensin converting enzyme inhibitor, beta-blocker, digoxin, and diuretic rapidly improved her cardiac condition. Repeat echocardiogram showed that the left ventricular function had improved substantially. The clinical condition of excess catecholaminemia (and thus, arterial hypertension and the abnormality of the glucose metabolism) subsided with complete resolution of the congestive heart failure following the surgical removal of the tumor. Evaluation for medullary thyroid carcinoma (MTC) revealed an elevated calcitonin level demonstrated by fine needle aspiration biopsy. There were no biochemical evidences for primary hyperparathyroidism. Multiple endocrine neoplasia 2 (MEN 2A) syndrome was diagnosed. An overwhelming secretion of catecholamine might cause severe cardiomyopathy and impair glucose metabolism, as evidenced by the improvement of both conditions following the medical treatment of catecholaminemia and surgical resection of the tumor.

Disseminated Medullary Thyroid Carcinoma Despite Early Thyroid Surgery in the Multiple Endocrine Neoplasia-2A Syndrome

A 51/2-year-old boy, with a family history of multiple endocrine neoplasia (MEN)-2A syndrome, was evaluated for presence of MEN-2A and medullary thyroid carcinoma (MTC). DNA diagnostics confirmed MEN-2A. Basal (360 ng/L) and pentagastrin stimulated (430 ng/L) calcitonin (CT) levels were slightly elevated, plasma carcinoembryonic antigen (CEA) was normal. Within a year both tumor markers increased and total thyroidectomy was performed. Histologic examination did not show MTC. In the following years, both tumor markers increased progressively but despite the use of multiple imaging techniques no metastases were localized. After 6 years, biopsy of a palpable lymph node showed MTC. The boy was treated with total cervical, suprahyoidal, and mediastinal lymph node dissection, showing MTC in almost all nodes. Again, the tumor markers remained high. At this point in time, the disadvantages of further medical interventions were outweighed against the chance for cure and it was decided to shift the goal of treatment toward palliation rather than cure. At the last visit the boy was clinically well with persistent extremely high levels of plasma CEA and CT. In conclusion, when prophylactic thyroidectomy in the MEN-2A syndrome has failed, it may be best to withdraw from further interventions to prevent more damage.

Novel germline mutation in the transmembrane region of RET gene close to Cys634Ser mutation associated with MEN 2A syndrome

Two mutations on the same allele of RET gene were revealed in a family with predisposition to multiple endocrine neoplasia (MEN) type 2A. The first mutation changes codon 634 from cysteine to serine. The second, a novel mutation in codon 641, changes alanine to serine in the transmembrane domain of the RET protein. Two mutations were present in close proximity in both the patients' germline and tumor DNA and were absent in DNA isolated from healthy family members and control blood donors. All MEN 2A affected family members suffered from medullary thyroid carcinoma and two of ten patients for pheochromocytoma. No parathyroid gland alterations were observed in patients with two RET gene mutations. Analysis of four genetic polymorphisms in the RET gene showed higher incidence of polymorphisms of exons 11 and 15. The observed allelic imbalance in favor of mutated allele in pheochromocytoma corresponded to higher expression of the RET gene. These observations confirm the multifactorial process leading to development of MEN 2A syndrome.

Multiple endocrine neoplasia 2A syndrome presenting as peripartum cardiomyopathy due to catecholamine excess

We report the case of a 24-year-old female with a history of medullary thyroid carcinoma who presented at 38 weeks gestation with acute chest pain and shortness of breath. She was found to be in pulmonary edema and respiratory failure. An emergency cesarean section was performed. Subsequently, an echocardiogram revealed an ejection fraction of 10%. After medical therapy with digoxin, milrinone, captopril and diuretics, her condition improved rapidly and a repeat echocardiogram showed that the left ventricular function had normalized. Diagnosis of pheochromocytoma was made by urine and plasma catecholamine measurements. Magnetic resonance imaging revealed a 3.7 cm left adrenal mass. Increased uptake activity was seen in the same region by an (131)I-metaiodobenzylguanidine (MIBG) scan. The patient underwent successful surgical resection of the pheochromocytoma. Subsequent DNA analysis revealed that the patient had a mutation of the RET proto-oncogene. The same mutation was also found in several of her family members. In summary, we report a case of multiple endocrine neoplasia 2A presenting as peripartum cardiomyopathy and cardiovascular collapse. Pheochromocytoma should be considered as a potential cause of peripartum cardiomyopathy.

Expression profiles provide insights into early malignant potential and skeletal abnormalities in multiple endocrine neoplasia type 2B syndrome tumors.

Identifying the molecular basis for genotype-phenotype correlations in human diseases has direct implications for understanding the disease process and hence for the identification of potential therapeutic targets. To this end, we performed microarray expression analysis on benign (pheochromocytomas) and malignant (medullary thyroid carcinomas, MTCs) tumors from patients with multiple endocrine neoplasia (MEN) type 2A or 2B, related syndromes that result from distinctive mutations in the RET receptor tyrosine kinase. Comparisons of MEN 2B and MEN 2A MTCs revealed that genes involved in the process of epithelial to mesenchymal transition, many associated with the tumor growth factor beta pathway, were up-regulated in MEN 2B MTCs. This MEN 2B MTC profile may explain the early onset of malignancy in MEN 2B compared with MEN 2A patients. Furthermore, chondromodulin-1, a known regulator of cartilage and bone growth, was expressed at high levels specifically in MEN 2B MTCs. Chondromodulin-1 mRNA and protein expression was localized to the malignant C cells, and its high expression was directly associated with the presence of skeletal abnormalities in MEN 2B patients. These findings provide molecular evidence that associate the previously unexplained skeletal abnormalities and early malignancy in MEN 2B compared with MEN 2A syndrome.

Multiple endocrine neoplasia 2A syndrome: Surgical management

Background/Purpose: Currently, molecular genetic diagnostics allow familial types of medullary thyroid carcinoma to be detected at an asymptomatic stage and surgery thus to be performed at a time when prognosis is good. The current report aims to determine the appropriate age for safe prophylactic thyroidectomy in children with multiple endocrine neoplasia (MEN) 2A and mutations at codon 609 according to genotype-phenotype correlations and will discuss surgical procedures. Methods: The authors describe the case of a family with hereditary MEN 2A syndrome. A DNA analysis of 7 family members confirmed the diagnosis by a mutation at codon 609 of the RET proto-oncogene. Results: A phaeochromocytoma developed in 2 family members. Four had medullary thyroid carcinoma. A grandson underwent a prophylactic thyroidectomy at the age of 5 on account of genetic evidence. Despite the negative preoperative and intraoperative findings he already had an invasive medullary thyroid carcinoma. Conclusions: Few genotype-phenotype correlations have been established for MEN 2A disease. According to the natural history of the disease, families with the genotype RET cys609gly should have a more benign disease than high-risk families (mutations at codon 634, 618). From this report the authors conclude that prophylactic thyroidectomy in “609” families should be performed earlier than actually recommended, favorably at the age of 2 to 4 years. Further multicenter studies are needed to provide more clinical and prognostic data for less frequent (codon 609, 630, 791, and 891) RET genotypes. J Pediatr Surg 37:897-900. Copyright 2002, Elsevier Science (USA). All rights reserved.

Role of the RET proto-oncogene in sporadic hyperparathyroidism and in hyperparathyroidism of multiple endocrine neoplasia type 2.

Parathyroid tumors occur either sporadically or as part of inherited syndromes such as multiple endocrine neoplasia (MEN) types 2A and 2B. The development of both of these familial syndromes has been related to specific germline gain-of-function mutations predominantly in exons 10 and 11 (MEN 2A) and 16 (MEN 2B) of the RET proto-oncogene. The same mutations have also been implicated in the pathogenesis of sporadic medullary thyroid carcinoma and sporadic pheochromocytoma. The RET mutations are thought to have a transforming effect only in cells of neural crest origin such as thyroid parafollicular (C-cells) and adrenal chromaffin cells, which normally express the RET proto-oncogene. Expression of RET messenger RNA has not yet been studied in the parathyroid, however, we demonstrate in this study by a sensitive, semiquantitative RT-PCR technique and in situ hybridization, that RET is expressed in MEN 2A parathyroid tumors and in sporadic adenomas. Although DNA from a parathyroid tumor of a MEN 2A patient displayed an expected mutation, none of the previously described MEN 2A or 2B mutations were found in DNA of 34 sporadic adenomas. Our data suggest that parathyroid disease is an integral part of the MEN 2A syndrome, but that MEN 2 mutations in RET rarely play a part in the pathogenesis of sporadic parathyroid tumors.