Multiple Endocrine Neoplasia 2B Syndrome Research Articles

Abstract 142: Endocrine neoplasia type 2B with a rare mutation: A case report

Introduction: Multiple Endocrine Neoplasia (MEN) type 2 is a rare familial endocrine syndrome. MEN 2B syndrome, the least common subtype of MEN 2 syndrome, is characterized by medullary carcinoma of thyroid (MTC), pheochromocytoma and absence of hyperparathyroidism. Identifying the responsible mutation have prognostic consequences. Majority of MEN2B cases occur due to de-novo mutation with 95% cases involving codon 918, and codon 883, 2-3% cases.Objective: Identification of the genetic mutation in patient presented with MTC, and bilateral adrenal pheochromocytoma.Methods: Whole Exome Analysis was performed to identify the genetic defect. The variants were prioritized using standard open-source computational pipelines.Results: Whole exome sequencing and computational analysis identified a non-synonymous single nucleotide polymorphism T1991C in the exon 13 of RET gene on chromosome 10, resulting in a missense mutation (p.M664T) in the protein responsible for phenotypic expression known as MEN 2B syndrome.Conclusion: MTC and bilateral pheochromocytoma are indications for detailed clinical and genetic examination of the proband. Bilateral adrenalectomy, followed by total thyroidectomy and prophylactic central neck dissection was done along with lifetime hormone supplementation. This is a rare mutation reported in MEN2B (A Rare Syndrome) which usually involve codon 918 and 883.

Incidental Colonic Ganglioneuroma on Surveillance Colonoscopy.

CASE REPORT A 73-year-old man with a history of diverticulitis after left hemicolectomy and an end-to-end colo-colonic anastomosis underwent a screening colonoscopy with resection of 4, 2-10-mm tubular adenomas. A 10-mm semipedunculated polyp with a normal mucosal pit pattern under narrow-band imaging was found in the splenic flexure (Figure 1). The polyp was resected using a hot snare and submitted for histopathological diagnosis, which demonstrated colonic mucosa with distorted crypt architecture. The lamina propria was expanded by collection of spindle cells within fibrillary matrix, and irregular nests and groups of ganglion cells indicated a ganglioneuroma (GN) (Figure 2). No clinical symptoms were associated with this finding, and a prior colonoscopy revealed no evidence of GN. Surveillance colonoscopy was recommended in 3 years, given the presence of an adenoma of ≥10 mm in size.Figure 1.: (A) A semipedunculated polyp under white-light imaging in the splenic flexure. (B) A semipedunculated polyp with a normal mucosal pit pattern under narrow-band imaging in the splenic flexure.Figure 2.: (A) An (H&E original magnification 20×) image of the colonic polyp consisting of abnormal appearing ganglion cells (single arrow) and spindled Schwann cells (double arrows). (B) An (H&E original magnification 10×) image of the colonic polyp consisting of abnormal appearing ganglion cells and spindled Schwann cells. H&E, hematoxylin & eosin.Ganglioneuromas of the gastrointestinal tract are rare tumors composed of ganglion cells, nerve fibers, and supporting cells. Gastrointestinal GNs are usually confined to the large intestine and are morphologically classified into 3 categories, namely, polypoid GNs, ganglioneuromatous polyposis, and diffuse ganglioneuromatosis.1 Polypoid GNs are mostly solitary and small (measuring <20 mm), with a sessile or pedunculated appearance. Colonic GNs are characterized by a normal colonic pit pattern under narrow-band imaging. These lesions produce no characteristic symptoms and are usually found incidentally during endoscopy. Rarely, they present with abdominal pain, obstruction, ileus, appendicitis, or weight loss depending on their size and anatomical location.2 Ganglioneuromatous polyposis and diffuse ganglioneuromatosis are associated with genetic syndromes, such as neurofibromatosis 1, multiple endocrine neoplasia 2B syndrome, and juvenile polyposis. Solitary GNs are generally not associated with familial syndromes, although they have been reported in cases of Cowden disease, tuberous sclerosis, polyposis coli, and juvenile polyposis.1 Gastrointestinal GNs are usually treated with endoscopic resection. Currently, no guidelines exist on the management of solitary GNs or recommendations for interval surveillance colonoscopy. Repeat colonoscopy is not necessary because of the benign nature of these lesions, which tend not to recur.3 DISCLOSURES Author contributions: S. Agarwal and Y. Wang designed and drafted the article and acquired data. PG Iyer drafted and revised the article for intellectual content. CL Leggett designed and drafted the article , acquired data, revised the article for important intellectual content, and is the article guarantor. Financial disclosure: None to report. Informed patient consent was obtained for this case report.

52-Year-Old Woman With Fever, Diaphoresis, and Abdominal Pain

52-Year-Old Woman With Fever, Diaphoresis, and Abdominal Pain

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.

The Relationship Between Palisaded Encapsulated Neuroma and the Mucocutaneous Neuroma Seen in Multiple Endocrine Neoplasia 2b Syndrome

A relationship between the palisaded encapsulated neuroma (PEN) and the mucocutaneous neuroma seen in multiple endocrine neoplasia (MEN) 2b syndrome has been noted. We experienced a case of multiple mucocutaneous neuromas including both MEN 2b type neuromas and PENs. We evaluated the histopathologic and immunohistochemical features of 48 lesions in this patient. The lesions were histopathologically classified into 3 groups: (1) MEN 2b type neuroma (18 lesions), (2) PEN (22 lesions), and (3) an intermediate form of the 2 conditions (8 lesions). The intermediate form was classified into 2 subtypes: 1 type characterized by PEN nodules made up of assembled neuroma fascicles neighboring MEN 2b type neuroma fascicles and the other type characterized by more broad nerve fascicles than those seen in typical MEN 2b type neuroma. The idea that PEN is a progressive form of MEN 2b type neuroma may be speculative. Instead, the present study suggests that the observation of hybrid MEN 2b type neuroma/PEN in association with MEN 2b type neuroma and PEN may be a characteristic finding in cases of multiple mucocutaneous neuromas. The view that MEN 2b type neuroma and PEN lie within a spectrum of the same disease entity may be an overstatement; however, the present study suggests that PEN is basically a neural hamartoma/benign neoplasm, like MEN 2b type neuroma, and that there is a close relationship between the 2 conditions in terms of their histogenesis.

Anaesthetic management of a dopamine-secreting phaeochromocytoma in multiple endocrine neoplasia 2B syndrome.

Anaesthetic management of a dopamine-secreting phaeochromocytoma in multiple endocrine neoplasia 2B syndrome.

Neural hyperplasia in maxillary bone of multiple endocrine neoplasia type 2B patient

Multiple endocrine neoplasia (MEN) type 2B is the rarest and most aggressive form of MEN syndrome. MEN 2B patients manifest characteristic oral and facial features besides the neural crest cell-derived tumors, including medullary carcinoma, pheochromocytoma, mucosal neuroma, and ganglioneuromatosis of the gut. We report a case of MEN 2B diagnosed on the basis of the warning signs of mucosal neuroma and multiple neural hyperplasias in the maxillary bone resected during orthognathic surgery. A subsequent systemic examination under the pathologic diagnosis of neural lesions revealed medullary thyroid carcinoma, megacolon, thickened corneal nerves, and RET gene mutation, thus verifying the diagnosis of MEN 2B. An immunohistochemical study revealed an increased number of unmyelinated Schwann cells in the hyperplastic nerves. We suggest that intraosseous neural hyperplasia is a specific finding of the MEN 2B syndrome in addition to the known oral and facial manifestations.

Metastatic Medullary Thyroid Cancer Presenting with Elevated Levels of CA 19-9 and CA 125

Calcitonin and carcinoembryonic antigen (CEA) are established markers of medullary thyroid cancer (MTC), used in the diagnosis and monitoring of disease and its progression. In clinical practice, various other tumor markers are utilized in the follow-up of different malignancies, although their utility has not been well described in MTC. CA 19-9 antigen, routinely used in the monitoring of pancreatic cancer, also has been detected in the tissue of approximately 6% of MTCs. However, its presence has never been reported in the serum of these patients. Elevation of CA 125 antigen, utilized as a tumor marker for ovarian cancer, has never been reported in MTC. We report a novel finding of metastatic MTC presenting with elevated CA 19-9 and CA 125 serum levels, with concurrent tissue staining for these antigens. A 56-year-old woman with multiple endocrine neoplasia 2B syndrome, post subtotal thyroidectomy for MTC in childhood, presented with extensive metastatic spread of MTC to the lungs and liver, 47 years after the original diagnosis. The patient's calcitonin level decreased from 2950 to 261 pg/mL (reference range: <20 pg/mL) over a 20-year period. The serum CEA level was elevated at 6800 ng/mL (reference range: <5.1 ng/mL). Because of a concern for an alternate malignancy, serum CA 19-9 and CA 125 tumor markers were measured and found to be significantly elevated, at 39,334 U/mL (reference range: <35.1 U/mL) and 96.2 U/mL (reference range: 7-41 U/mL), respectively. Immunostaining of the metastatic MTC tissue showed patchy staining for calcitonin, strongly positive staining for CEA and CA 19-9, and weakly positive staining for CA 125. Drawing from experience with CA 19-9 and CA 125 tumor markers in other malignancies, we propose that they may be associated with aggressive forms of MTC with significant metastatic potential.

The optimal age for performing surgery on patients with MEN 2B syndrome

Multiple endocrine neoplasia (MEN) syndromes are characterized by the association of various endocrine neoplasias. Prophylactic thyroidectomy is the treatment of choice for patients with RET gene mutations. The age at which patients undergo prophylactic thyroidectomy may vary depending on the position of the RET gene codon. In cases of MEN2B, when the mutation is carried in codons 883, 918 or 922, prophylactic thyroidectomy is performed prior to 6months of age, due to the increased aggressiveness of these heterozygosities, which are capable of determining the onset of medullary cancer during the first months of life. We present two heterozygous twin patients with MEN 2B syndrome who were born 32weeks premature, and who underwent prophylactic thyroidectomy at 7months of age. The patients were carriers of the mutation at codon 918. We suggested the early surgery at 7months as, due to their prematurity, the patients were required to gain weight to improve their condition prior to surgery. The two patients had medullary thyroid carcinoma without lymph node involvement. In conclusion, for a truly prophylactic thyroidectomy, such patients should undergo surgery within the first month of life, particularly if these patients are carriers of the mutation in codons 883, 918 or 922.

Bilateral submandibular gland oncocytoma in a patient with multiple endocrine neoplasia 2B syndrome and neurofibromatosis type 1: an unusual case

Oncocytomas are unusual neoplasms of the head and neck that occur mainly in the parotid gland. The authors report a case of bilateral submandibular gland oncocytoma in a patient with multiple endocrine neoplasia 2B syndrome and neurofibromatosis type 1. Histopathology of the resection specimens demonstrated lymphovascular invasion but no other aggressive features. This was a highly unusual feature in an otherwise rare benign tumour.

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.

Medullary thyroid carcinoma in a 2-month-old male with multiple endocrine neoplasia 2B and symptoms of pseudo-Hirschsprung disease: a case report

A 5-week-old male patient was seen for symptoms suggestive of Hirschsprung disease (abdominal distension, failure to thrive, and explosive defecation). Rectum biopsies revealed an intestinal ganglioneuromatosis, which is usually associated with multiple endocrine neoplasia (MEN) syndrome type 2B. The ensuing molecular genetic analysis revealed a M918T mutation of the RET protooncogene, which is associated with early-onset medullary thyroid carcinoma (MTC). Therefore, total thyroidectomy and central lymphadenectomy were performed at the age of 9 weeks. Histology showed a medullary microcarcinoma. This report of MTC occurrence within the first weeks of life underlines the importance of early diagnosis and thyroidectomy in patients with MEN 2B syndrome. Because many patients with MEN 2A and B show gastrointestinal symptoms before the development of MTC, the possibility of MEN 2 should be recognized, and genetic testing for the presence of RET mutations should be included in the explorative diagnosis for megacolon.

Multiple Endocrine Neoplasia 2B Syndrome due to Codon 918 Mutation: Clinical Manifestation and Course in Early and Late Onset Disease

More than 50% of patients with typical MEN-2B have a de novo M918T germline mutation of the RET protooncogene. However, even in typical MEN-2B, extrathyroidal manifestations of MEN-2B can be found to be differently expressed. We analyzed the clinical manifestation and course in 21 patients harboring a de novo RET M918T mutation. Mean age at MEN-2B diagnosis was 14.2 years (range: 1-31 years). All patients had medullary thyroid carcinoma (MTC). At the time of syndrome diagnosis, oral manifestations (bumpy lips, ganglioneuroma), ocular manifestations (corneal fibers, conjunctivitis sicca), intestinal dysfunctions, musculoskeletal manifestations, and pheochromocytoma were found in 86%, 90%, 74%, 79%, and 19% of the patients, respectively. At the time of follow-up examination, the symptoms were found at higher frequency. Severe intestinal manifestation was predominantly found in patients with prepubertal onset (< or = 12 years) of MTC (n = 4/10) compared with patients with late onset (> 12 years) of MTC (n = 0/11) (40% versus 0%; p = 0.019). Although biochemical cure was found only in four patients with early onset of MTC, the long-term prognosis for patients with early onset of MTC was poorer than for patients presenting with late onset of MTC (p = 0.005). During mean follow-up of 55.8 months (range: 3-161 months), seven patients (33%) died from MTC. In conclusion, whereas most typical MEN-2B symptoms were found to be age-related, severe intestinal manifestation was found to be predominantly expressed in patients with early onset of MTC. Furthermore, in patients with early onset of MTC who could not be biochemically cured, the long-term prognosis was found to be worse than that of non-cured patients with late onset of MTC, suggesting an additional pathological process in the younger subgroup reinforcing the very high transforming in vitro activity of the M918T RET mutation.

Prophylactic thyroidectomy in multiple endocrine neoplasia: the impact of molecular mechanisms of RET proto-oncogene.

Multiple endocrine neoplasia (MEN) type 2, a cancer syndrome inherited in the dominant fashion, is defined by the occurrence of medullary thyroid carcinoma (MTC), either as a singular lesion (familial medullary thyroid carcinoma, FMTC) or with the variable expression of pheochromocytoma, hyperparathyroidism (MEN 2A), ganglioneuromas, buccal neuromas and Marfanoid-like phenotype (MEN 2B). Germline mutations of the RET proto-oncogene, localized on chromosome 10q11.2, have been identified as the underlying genetic cause of the disorder. In the majority of patients with MEN 2A/FMTC missense mutations at exon 10 or exon 11 are identifiable. Cysteine to arginine exchange at codon 634 is the mutation most frequently found. In MEN 2B approximately 95% of patients present with a mutation at codon 918 (exon 16). Additionally, less frequent mutations in other codons have been found in both syndromes. The DNA-based genotype analysis enables the identification of gene carriers at risk of developing MTC and offer them prophylactic thyroidectomy prior to development of any thyroid pathologies. Prophylactic surgery is generally recommended for MEN 2A/FMTC gene carriers at the age of 4-6 years. Due to the aggressiveness of the MEN 2B syndrome gene carriers should be operated by the age of 1 year. Presumably some less virulent mutations allow postponement of the prophylactic treatment to the second to fourth decade of life. Compared to standard presymptomatic biochemical screening, genetic testing and consecutive prophylactic treatment contribute to better outcome of individuals at risk for MTC.

Typical ocular findings in a patient with multiple endocrine neoplasia type 2b syndrome

Multiple endocrine neoplasia (MEN) type 2b syndrome is accompanied by typical ocular findings; however, the disease is often only diagnosed at an advanced stage by symptoms of C-cell carcinoma or pheochromocytoma and is then fatal in most cases. Therefore, the importance of ophthalmic assessment in making the diagnosis has to be stressed. The history and ocular findings of a patient with MEN 2b syndrome are described, and a brief overview of the syndrome is given. Slit-lamp examination showed extremely thickened corneal nerves as well as multiple small plexiform and nodular subconjunctival tumors. Both eyes also displayed thickened upper and lower eyelids. A molecular genetic study of the RET proto-oncogene showed a heterozygous ATG to ACG mutation in codon 918 of exon 16. Greatly thickened corneal nerves and subconjunctival tumors may be the first hint of MEN 2b. Whenever greatly thickened corneal nerves are detected, MEN 2b must be ruled out.