Early detection of multiple endocrine neoplasia type 1: A case report

BACKGROUND Multiple endocrine neoplasias(MENs)are a group of hereditary diseases invol-ving multiple endocrine glands,and their prevalence is low.MEN type 1(MEN1)has diverse clinical manifestations,mainly involving the parathyroid glands,gastrointestinal tract,pancreas and pituitary gland,making it easy to miss the clinical diagnosis.CASE SUMMARY We present the case of a patient in whom MEN1 was detected early.A middle-aged male with recurrent abdominal pain and diarrhea was admitted to the hos-pital.Blood tests at admission revealed hypercalcemia and hypophosphatemia,and emission computed tomography of the parathyroid glands revealed a hy-perfunctioning parathyroid lesion.Gastroscopy findings suggested a duodenal bulge and ulceration.Ultrasound endoscopy revealed a hypoechoic lesion in the duodenal bulb.Further blood tests revealed elevated levels of serum gastrin.Surgery was performed,and pathological analysis of the surgical specimens revealed a parathyroid adenoma after parathyroidectomy and a neuroendocrine tumor after duodenal bulbectomy.The time from onset to the definitive diagnosis of MEN1 was only approximately 1 year.CONCLUSION For patients who present with gastrointestinal symptoms accompanied by hyper-calcemia and hypophosphatemia,clinicians need to be alert to the possibility of MEN1.

C634Y mutation in RET-induced multiple endocrine neoplasia type 2A:A case report

BACKGROUND Multiple endocrine neoplasia type 2(MEN2)is a rare,autosomal dominant endocrine disease.Currently,the RET proto-oncogene is the only gene implicated in MEN2A pathogenesis.Once an RET carrier is detected,family members should be screened to enable early detection of medullary thyroid carcinoma,pheochromocytoma,and hyperparatitity.Among these,medullary thyroid carcinoma is the main factor responsible for patient mortality.Accordingly,delineating strategies to inform clinical follow-up and treatment plans based on genes is paramount for clinical practitioners.CASE SUMMARY Herein,we present RET proto-oncogene mutations,clinical characteristics,and treatment strategies in a family with MEN2A.A family study was conducted on patients diagnosed with MEN2A.DNA was extracted from the peripheral blood of family members,and first-generation exon sequencing of the RET protooncogene was conducted.The C634Y mutation was identified in three family members spanning three generations.Two patients were sequentially diagnosed with pheochromocytomas and bilateral medullary thyroid carcinomas.A 9-yearold child harboring the gene mutation was diagnosed with medullary thyroid carcinoma.Surgical resection of the tumors was performed.All family members were advised to undergo complete genetic testing related to the C634Y mutation,and the corresponding treatments administered based on test results and associated clinical guidelines.CONCLUSION Advancements in MEN2A research are important for familial management,assessment of medullary thyroid cancer invasive risk,and deciding surgical timing.

Improving early diagnosis of multiple endocrine neoplasia type 1 by assessing the gastrointestinal symptoms,hypercalcemia,and elevated serum gastrin

Despite advancements in the field,early diagnosis of multiple endocrine neoplasia type 1(MEN1)remains unachievable.This letter to the editor highlighted the importance of carefully assessing gastrointestinal symptoms,hypercalcemia,and elevated serum gastrin levels,as suggested by Yuan et al in their paper.They focused on a patient with recurrent abdominal pain and diarrhea whose diagnostic path led to establishing a MEN1 diagnosis within a year.This emphasized the need for clinicians to consider MEN1 in patients with similar presentations,particularly when gastrointestinal symptoms persist or recur after discontinuation of proton pump inhibitors,especially knowing that early recognition and intervention are crucial for improving patient outcomes.

Molecular diagnostic approaches in detecting rearranged during transfection oncogene mutations in multiple endocrine neoplasia type 2

Different types of neuroendocrine cancer,including medullary thyroid cancer(MTC)and thyroid C-cell hyperplasia,are part of multiple endocrine neoplasia type 2(MEN2).A proto-oncogene mutation of the rearranged during transfection(RET)gene changes the way that receptor tyrosine kinases work.Multiple endocrine neoplasia,a pathological condition,involves these kinases.When the RET protooncogene changes,it can cause endocrine adenomas and hyperplasia to happen at the same time or one after the other.Pheochromocytoma,medullary thyroid carcinoma,and hyperparathyroidism,alone or in combination,are present in MEN2A patients.Some patients may also have skin lichen amyloidosis or Hirschsprung's disease.Patients with MEN2A often present with MTC.MTC is aggressive and has the worst prognosis,as most patients exhibit lymph node metastasis.MTC is one of the important causes of death in patients with MEN2A.RET mutation analysis aids in identifying MEN2A symptoms and monitoring levels of calcium,thyroid hormones,calcitonin,normetanephrine,fractionated metanephrines,and parathyroid hormone.The earlier diagnosis of MTC significantly improves survival and prompts better management of MEN2A.In this editorial,we will discuss the significance of molecular diagnostic approaches in detecting RET oncogene mutations in MEN2A.

Biochemically curative surgery for gastrinoma in multiple endocrine neoplasia type 1 patients

AIM： To search for the optimal surgery for gastrinoma and duodenopancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1. METHODS： Sixteen patients with genetically confirmed multiple endocrine neoplasia type 1 （MEN 1） and Zollinger-Ellison syndrome （ZES） underwent resection of both gastrinomas and duodenopancreatic neuroendocrine tumors （NETs） between 1991 and 2009. For localization of gastrinoma, selective arterial secretagogue injection test （SASI test） with secretin or calcium solution was performed as well as somatostatin receptor scintigraphy （SRS） and other imaging methods such as computed tomography （CT） or magnetic resonance imaging （MRI）. The modus of surgery for gastrinoma has been changed over time, searching for the optimal surgery： pancreaticoduodenectomy （PD） was first performed guided by localization with the SAST test, then local resection of duodenal gastrinomas with dissection of regional lymph nodes （LR）, and recently pancreas-preserving total duodenectomy （PPTD） has been performed for multiple duodenal gastrinomas. RESULTS： Among various types of preoperative localizing methods for gastrinoma, the SASI test was the most useful method. Imaging methods such as SRS or CT made it essentially impossible to differentiate functioning gastrinoma among various kinds of NETs. However, recent imaging methods including SRS or CT were useful for detecting both distant metastases and ectopic NETs; therefore they are indispensable for staging of NETs. Biochemical cure of gastrinoma was achieved in 14 of 16 patients （87.5%）; that is, 100% in 3 patients who underwent PD, 100% in 6 patients who underwent LR （although in 2 patients （33.3%） second LR was performed for recurrence of duodenal gastri- noma）, and 71.4% in 7 patients who underwent PPTD. Pancreatic NETs more than 1 cm in diameter were resected either by distal pancreatectomy or enucleations, and no hepatic metastases have developed postoperatively. Pathological study of the resected specimens revealed co-existence of pancreatic gastrinoma with duodenal gastrinoma in 2 of 16 patients （13%）, and G cell hyperplasia and/or microgastrinoma in the duodenal Brunner＇s gland was revealed in all of 7 duodenal specimens after PPTD. CONCLUSION： Aggressive resection surgery based on accurate localization with the SASI test was useful for biochemical cure of gastrinoma in patients with MEN 1.Imamura Metal. Curative resection of gastrinoma in MEN-1

Comprehensive treatment of rare multiple endocrine neoplasia type 1:A case report

BACKGROUND Multiple endocrine neoplasia type 1(MEN1)is a rare hereditary disorder caused by mutations of the MEN1 gene.It is characterized by hyperparathyroidism and involves the pancreas,anterior pituitary,duodenum,and adrenal gland.Here,we report a 40-year-old male patient with MEN1 who first manifested as thymic carcinoid,then primary hyperparathyroidism and prolactinoma,and a decade later pancreatic neuroendocrine tumor.CASE SUMMARY The patient underwent a thymectomy because of the thymic carcinoid 10 years prior and a prolactinoma resection 2 years prior.His sister suffered from prolactinoma.His parents displayed a typical triad of amenorrhea,galactorrhea,and infertility.Computed tomography revealed a strong signal in the upper portion of the left lobes and posterior portion of the right lobes of the thyroid and irregular soft tissue densities of the pancreatic body.Positron emission tomography/computed tomography imaging further showed strong 18Fflurodeoxyglucose uptake in the tail of the pancreatic body and segment IV of the liver.The patient underwent pancreatic body tail resection,pancreatic head mass enucleation,and ultrasound-guided radio-frequency ablation for liver cancer.Pathology results reported neuroendocrine tumor grade 2.Whole exome sequencing revealed a verified pathogenic mutation c.378G>A(p.Trp126*)in the MEN1 gene.The diagnosis of MEN1 was confirmed.At the 1.5-year follow-up,the patient appeared healthy without any sign of reoccurrence.CONCLUSION The present case may add some insight into the diagnosis and treatment of patients with MEN1.

Multiple endocrine neoplasia type 1 combined with thyroid neoplasm:A case report and review of literatures

BACKGROUND Multiple endocrine neoplasia type 1(MEN1)is a rare hereditary tumor syndrome inherited in an autosomal dominant manner and presents mostly as parathyroid,endocrine pancreas(such as gastrinoma)and anterior pituitary tumors.At present,papillary thyroid carcinoma(PTC)and nodular goiter are not regarded as components of MEN1.CASE SUMMARY A 35-year-old woman presented with MEN1 accompanied by coinstantaneous PTC and nodular goiter.The pathological diagnosis was PTC with cervical lymph node metastasis,nodular goiter,parathyroid cyst and adenomatoid hyperplasia.Genetic testing was performed and a MEN1 gene mutation was detected.The patient underwent unilateral lobectomy of the thyroid gland and surgical removal of the parathyroid tumors.At 18 mo of follow-up,ultrasonic examination of the neck showed no abnormality.Serum calcium and parathyroid hormone levels were normal.No new MEN1-associated tumors were detected.CONCLUSION The role of inactivating mutations of MEN1 gene in tumorigenesis of PTC and/or nodular goiter remains to be determined by more case reports and further research.

A NOVEL Ser73Gly VARIATION OF SUCCINATE DEHYDROGENASE,SUBUNIT D AND A Cys634Gly MUTATION IN Ret PROTO-ONCOGENE OBSERVED IN A CHINESE MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A PATIENT

Multiple endocrine neoplasia type 2A （ MEN2A ） is an autosomal dominant cancer syndrome that is characterized by medullary thyroid carcinoma （MTC）, pheochromaocytoma （50% - 60% of cases ）, and hyperplasia of the parathyroid glands （ 20% - 30% of cases ）. MEN-2A comprises a heterogeneous group of neoplastic disorders that most commonly have a single missense substitution of the Ret proto-oncogene （RET） involving exons 10 and 11. Here, we reported a novel case of MEN2A associated with two variations in two distinct genes, Cys634Gly in RET and a rare Ser73Gly substitution in succinate dehydrogenase, subunit D （SDHD）. Because the patient presented with medullary thyroid carcinoma and pheochromocytoma but without parathyroid gland involvement, we speculated that this clinical feature could be correlated with the two substitutions. This is the first report of a MEN2A case involving two different changes one in the RET gene and the other in the SDHD gene.

RET proto-oncogene mutation analysis in a pedigree with multiple endocrine neoplasia 2A

Objective To discuss clinical diagnosis and treatment of multiple endocrine neoplasia ( MEN) 2A,and report the mutation of RET proto-oncogene in a pedigree of three patients with MEN 2A. Methods Bilateral adrenalectomy was performed on two of the three

Diagnosis and surgical treatment of multiple endocrine neoplasia

Background Multiple endocrine neoplasia （MEN） is relatively rare. But more patients could be found by detailed examination. We discuss the diagnosis and surgical treatment of MEN. Methods The clinical data of 95 MEN cases were retrospectively analyzed. There were 30 cases of MEN1 including 19 cases from 6 families. The MEN1 gene mutation was detected in 81.48% of cases admitted after 1997. There were 22 cases of primary hyperparathyroidism （PHPT）, 10 cases of enteropanceatic tumor including 9 cases of insulinoma, 15 cases of pituitary adenoma, 9 cases of adrenal adenoma, 2 cases of thymic carcinoid. Two patients had 4 glands involved, 3 patients had 3 glands involved, 16 patients had 2 glands involved, and 6 patients had only one gland involved. Three patients had neither clinical symptoms nor biochemical changes, and was diagnosed by MEN1 gene mutation. Six patients presented with nephrolithasis and 6 patients had impaired pancreatic endocrine function. There were 60 cases of MEN2a and 5 cases of MEN2b. 58 cases of MEN2a belongs to 19 kindreds. All MEN2a patients but one presented RET gene mutation in codon 634, and all MEN2b cases had mutation in codon 918.48 cases of MEN2a had thyroid masses with elevated calcitonin levels. 27 patients had pheochromocytoma including 12 cases of multiple foci and 5 malignancy. 13 patients presented with hyperparathyroidism. 5 MEN2b patients had medullary thyroid carcinoma and mucosal ganglioneuromatosis with Marfanoid. Among them, 3 patients had bilateral pheochromocytoma. Results In MEN1, subtotal parathyroidectomy was performed in 12 patients with PHPT and one patient received parathyroid adenoma enucleation. Insulinomas were enucleated in 4 patients. Two patients underwent thymus tumor extirpation. Total thyroidectomy with bilateral dissection of regional lymph nodes was performed in 16 patients with MEN2a and nodule enucleation was performed in 9 patients. Twenty two MEN2a patients underwent pheochromocytoma enucleation including bilateral adrenal resection in 10 cases. 5 MEN2b patients underwent total thyroidectomy with bilateral lymph node dissection. Among them, 3 cases underwent bilateral adrenal operations. Conclusions MEN varies in symptoms. Germline mutation test is helpful in establishing a diagnosis. Surgical management should be aimed at the improvement of life quality in MEN1 and prevention of the fetal tumors in MEN2.

Mutation analysis in a Chinese family with multiple endocrine neoplasia type 1

Background Multiple endocrine neoplasia type 1 （MEN1） by germline mutations of the tumor suppressor gene MEN1. with MEN1. Methods A large Chinese family with MEN1 was collected MEN1 gene were amplified and sequenced. is an autosomal dominant cancer syndrome which is caused This study aimed to identify mutations in a Chinese pedigree All of the coded regions and their adjacent sequences of the Results In this family, a heterozygous cytosine insertion in exon 10 （c.1546_1547insC） inducing a frame shift mutation of MEN1 was found in the proband and the other two suffering members of his family. This mutation was linked to a novel single nucleotide polymorphism （SNP）in intron 3 （IVS3＋18C〉T）. Conclusions The mutation in exon 10 of MEN1 gene might induce development of parathyroid hyperplasia and pituitary adenoma and cosegregate with MEN1 syndrome. The significance of the new found IVS3＋18C〉T of MEN1 needs a further investigation.

MULTIPLE ENDOCRINE NEOPLASIA TYPE IIB REPORT OF A CASE

Multiple endocrine neoplasia (MEN) type IIb,called also MEN III or mucosal neuroma syndrome,is a rare condition. A typical case confirmed by au-topsy is here reported and discussed briefly.CASE REPORTA 27-year-old male patient complained of fre-quent epigastric pain and diarrhea for 12 years. Atthe age of 21, he had a biopsy of a papillary lesionin his eyelids, and histological examination con-firmed the diagnosis of mucosal neuromas. Twoyears later, subtotal gastrectomy was done for a sus-pected perforated peptic ulcer at a local hospital. Ex-ploration showed an ulcer at the gastric antrum andanother at the duodenal bulb and hypertrophicgastritis and proliferation of the parietal cells werefound histologically. Postoperatively, diarrhea per-sisted and epigastric distention appeared. On Septem-ber 12,1990, the patient was referred to ourhospital.

The expression of p27^(Kip1) and β-catenin in multiple endocrine neoplasia type 1-related parathyroid tumors

Objective To explore tissue expression of cyclin-dependent kinase inhibitor p27Kip1 andβ-catenin in multiple endocrine neoplasia type1（MEN1）-related parathyroid tumors（MHPT）.Methods Immunohistochemistry was performed to analyze the expression of p27Kip1 andβ-catenin in parathyroid glands from 31 subjects

Occult Adrenal Insufficiency in Patients with Chronic Renal Disease

Background: Addison’s disease is a rare disorder of the adrenal cortex that leads to inadequate production of cortisol initially followed by aldosterone and androgens. Its manifestations are usually slow and non-specific with potential for life-threatening adrenal crisis following hypermetabolic demands (infection, trauma, surgery). Patients: Over the past 10 years, 19 CRD-patients were diagnosed with occult PAI in our center. Results: Unprovoked hypotension was the most common manifestations of occult PAI and was the unmasking event in 11 (58%). It was without significant cardiac and/or severe systemic sepsis and was refractory to isotonic saline infusions. Equal number of the remaining patients (n = 2) presented with persistent and inexplicable electrolytes abnormalities viz. 1) hyponatremia despite restricted oral fluid intake, lack of dehydration and massive fluid overload, as well as 2) hyperkalemia despite potassium-restricted diet, hyperkalemic drugs and adequate therapy with Furosemide and low-potassium dialysis-baths. On the other hand, similar proportions presented with unprovoked 3) progressive weight loss, decrease appetite and cachexia as well as 4) frequent hypoglycemic attacks. All patients were treated and were medically stable after 29 (2 - 60) months of follow up. Autoantibodies to 21-hydroxylase enzyme were positive in 16 (90%). At diagnosis, and subsequent follow up, only 7 patients (37%) had multi-endocrine dysfunction of whom 2 with type 1 and 5 with type 2. Conclusion: High index of suspicion should be exerted in diagnosis of PAI in patients with CRD, since its clinical picture is similar to CRD manifestations and complications. In those patients, confirmatory tests and specific management can save their lives. .

Sporadic versus hereditary gastrinomas of the duodenum and pancreas: Distinct clinico-pathological and epidemiological features

Gastrinomas are defined as gastrin secreting tumors that are associated with Zollinger-Ellison syndrome （ZES）. ZES is characterized by elevated fasting gastrin serum levels, positive secretin stimulation test and clinical symptoms such as recurrent peptic ulcer disease, gastroesophageal reflux disease and occasional diarrhea. Genetically, nonhereditary （sporadic） gastrinomas are distinguished from hereditary gastrinomas, which are associated with multiple endocrine neoplasia type 1 （MEN1） syndrome. In general, duodenal gastrinomas are small and solitary if they are sporadic and multiple as well as hereditary. The sporadic gastrinomas occur in the duodenum or in the pancreas while the hereditary gastrinomas almost all occur in the duodenum. Our series of 77 sporadic duodenal neuroendocrine tumors （NETs） includes 18 patients （23.4%） with gastrinomas and ZES. Of 535 sporadic NETs in the pancreas collected from the NET archives of the departments of pathology in Zürich, Switzerland, and Kiel, Germany, 24 patients （4.5%） suffered from sporadic pancreatic gastrinomas and ZES. These NETs have to be distinguished from tumors with immunohistochemical positivity for gastrin but without evidence of ZES. An additional 19 patients suffered from MEN1 and ZES. These patients showed exclusively duodenal gastrinomas, but not pancreatic gastrinomas. The prognosis of sporadic and MEN1- associated duodenal gastrinomas is better than that of pancreatic gastrinomas, since they progress slowly to liver metastasis. In summary, sporadic and MEN1- associated gastrinomas in the duodenum and pancreas show different clinico-pathological and genetic features. The incidence of sporadic duodenal gastrin-producing tumors is increasing, possibly due to optimized diagnostic procedures. In contrast, pancreatic MEN1- associated gastrinomas seem to be extremely rare. A considerable subset of tumors with immunohistochemical expression of gastrin but without evidence of ZES should be designated as functionally inactive NETs expressing gastrin, but not as gastrinomas.

Is new American Thyroid Association risk classification for hereditary medullary thyroid carcinoma applicable to Chinese patients? A single-center study

Objective: The American Thyroid Association (ATA) proposed a new risk classification for hereditary medullary thyroid carcinoma (MTC) in 2015. This study aimed to assess whether the new guidelines are suitable for the Chinese population, and reported our experience on prophylactic thyroidectomy. Methods: A total of 73 patients from 22 families were screened as rearranged during transfection (RET) mutation carriers from 2010 to 2016 in Cancer Hospital, Chinese Academy of Medical Science; the medical history for each patient was collected. Based on the initial treatment, we identified the risk factors for poor prognosis by univariate and multivariate logistic regression. Then, 4 RET mutation carriers were enrolled for prophylactic thyroidectomy, and their pathological data and follow-up outcomes were recorded. Results: In univariate and multivariate logistic regression analyses, age at initial surgery and risk classification were significant risk factors for stage III/IV hereditary MTC at initial diagnosis. The likelihood was increased by 11.6% per year of age at initial surgery [95% confidence interval (95% CI), 1.040-1.198; P=0.002). It was 7.888 times more likely to have III/IV stage disease for ATA highest risk patients, compared to ATA moderate risk individuals (95% CI, 1.607-38.717; P=0.003). Postoperative pathological results showed all 4 multiple endocrine neoplasia type 2A (MEN2A) patients had C-cell hyperplasia (CCH); multifocal malignancies were detected in 3 of them. All 4 patients were cured biochemically, and none developed permanent hypoparathyroidism. Conclusions: In Chinese individuals, hereditary MTC aggressiveness is in line with the new ATA risk classification. Germline RET gene mutation carriers should undergo prophylactic thyroidectomy according to basal serum calcitonin levels.

Hyperinsulinemic hypoglycemia due to adult nesidioblastosis in insulin-dependent diabetes

In neonates, persistent hyperinsulinemic hypoglycemia (PHH) is associated with nesidioblastosis. In adults, PHH is usually caused by solitary benign insulinomas. We report on an adult patient who suffered from insulin-de- pendent diabetes mellitus, and subsequently developed PHH caused by diffuse nesidioblastosis. Mutations of the MEN1 and Mody 2/3 genes were ruled out. Preoperative diagnostic procedures, the histopathological criteria and the surgical treatment options of adult nesidioblastosis are discussed. So far only one similar case of adult nesidioblastosis subsequent to diabetes mellitus Ⅱ has been reported in the literature. In case of conversion of diabetes into hyperinsulinemic hypoglycemia syndrome, nesidioblastosis in addition to insulinoma should be con- sidered.

Vasoactive intestinal peptide secreting tumour:An overview

Vasoactive intestinal peptide(VIP)secreting tumour(VIPoma)is a rare functional neuroendocrine tumour that typically arises from pancreatic islet cells.These present as sporadic,solitary pancreatic neoplasias with an estimated incidence of one in ten million individuals per year.Only around 5%of VIPomas are associated with multiple endocrine neoplasia type I syndrome.Excessive VIP secretion produces a clinical syndrome characterized by refractory watery diarrhoea,hypokalemia and metabolic acidosis.These coupled with elevated plasma levels of VIP are diagnostic.The majority of VIPomas are malignant and have already metastasized at the time of diagnosis(60%).Metastases occur most frequently in the liver,or regional lymph nodes,lungs,kidneys and bones.Some reports of skin metastases have been documented.Complete surgical resection continues to be the only potentially curative treatment.However,when the neoplasia cannot be excised completely,surgical debulking may provide palliative benefit.Other palliative options have included recently the peptide receptor radionuclide therapy which has shown to be effective and well-tolerated.This article will review all aspects of pancreatic VIPomas highlighting aspects such as clinical presentation,diagnosis and management.

Molecular alterations and therapeutic targets in pancreatic neuroendocrine tumors

Human pancreatic neuroendocrine tumors(PanNETs)are a rare,deadly tumor type that is sporadic or arises in the background of a hereditary syndrome.A critical genetic event in sporadic tumors is inactivation of the gene menin 1(MEN1)on chromosome 11,and indeed,PanNETs occur in patients with the hereditary syndrome multiple endocrine neoplasia type 1(MEN1)due to germline mutations in the gene.Here,we review the recent progress in the field of molecular genetics and therapeutic targets of PanNETs.The key genomic alterations,including MEN1,ATRX/DAXX,mammalian target of rapamycin(mTOR),DNA damage and repair associated genes,vascular endothelial growth factor receptor(VEGFR)and SSTRs,and epigenetic aberrations in PanNETs are discussed.In addition,the commonly used preclinical models for PanNETs are enumerated.