Occult insulinoma with treatment refractory, severe hypoglycaemia in multiple endocrine neoplasia type 1 syndrome; difficulties faced during diagnosis, localization and management; a case report.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN 1) syndrome is a rare, complex genetic disorder characterized by increased predisposition to tumorigenesis in multiple endocrine and non-endocrine tissues. Diagnosis and management of MEN 1 syndrome is challenging due to its vast heterogeneity in clinical presentation. CASE PRESENTATION: A 23-year-old female, previously diagnosed with Polycystic Ovarian Syndrome (PCOS) and pituitary microprolactinoma presented with drowsiness,confusion and profuse sweating developing over a period of one day. It was preceded by fluctuating, hallucinatory behavior for two weeks duration. There was recent increase in appetite with significant weight gain. There was no fever, seizures or symptoms suggestive of meningism. Her Body mass index(BMI) was 32 kg/m2.She had signs of hyperandrogenism. Multiple cutaneous collagenomas were noted on anterior chest and abdominal wall. Her Glasgow Coma Scale was 9/15. Pupils were sluggishly reactive to light. Tendon reflexes were exaggerated with up going planter reflexes. Moderate hepatomegaly was present. Rest of the clinical examination was normal. Laboratory evaluation confirmed endogenous hyperinsulinaemic hypoglycaemia suggestive of an insulinoma. Hypercalcemia with elevated parathyroid hormone level suggested a parathyroid adenoma. Presence of insulinoma, primary hyperparathyroidism and pituitary microadenoma, in 3rd decade of life with characteristic cutaneous tumours was suggestive of a clinical diagnosis of MEN 1 syndrome. Recurrent, severe hypoglycaemia complicated with hypoglycaemic encephalopathy refractory to continuous, parenteral glucose supplementation and optimal pharmacotherapy complicated the clinical course. Insulinoma was localized with selective arterial calcium stimulation test. Distal pancreatectomy and four gland parathyroidectomy was performed leading to resolution of symptoms. CONCLUSIONS: Renal calculi or characteristic cutaneous lesions might be the only forewarning clinical manifestations of an undiagnosed MEN 1 syndrome impending a life-threatening presentation. Comprehensive management of MEN 1 syndrome requires multi-disciplinary approach with advanced imaging modalities, advanced surgical procedures and long-term follow up due to its heterogeneous presentation and the varying severity depending on the disease phenotype.

Is Routine Screening of Young Asymptomatic MEN1 Patients Necessary?

BACKGROUND: Recent clinical practice guidelines recommend that routine screening of MEN1 mutation carriers should start at the age of 5 years. The occurrence of clinically relevant MEN1 organ manifestations in children (≤18 years) was evaluated. METHODS: Two prospective collected databases of MEN1 patients (n = 166) who underwent annual screening were retrospectively analyzed for organ manifestations in MEN1 patients ≤18 years. The follow-up was based on the most recent screening examination until December 2015. RESULTS: Twenty [11 females, 9 males, (12%)] of 166 MEN1 patients were diagnosed with at least one organ manifestation at age ≤18 years. The most frequent manifestation was mild asymptomatic pHPT (n = 9, 45%, age range 8-18 years). Eight (40%) young patients had pNENs (three non-functioning pNENs, five insulinomas, age range 9-18 years). All five insulinomas were diagnosed based on hypoglycemic symptoms. The other organ manifestations were asymptomatic pituitary adenomas in six patients (30%, age range 15-18 years) and a bronchial carcinoid in one 15-year-old patient. Only six (30%) patients ≤18 years had clinically relevant organ manifestations. CONCLUSION: Symptomatic or severe manifestations in MEN1 patients rarely occur below the age of 16 years. With regard to psychological burden and cost-effectiveness, routine screening of asymptomatic MEN1 patients should be postponed at least until the age of 16 years.

[Multiple Endocrine Neoplasia I (Wermers Syndrome), Forms of Clinical Manifestation, 5 Case Studies]. / Mnohocetná endokrinní neoplazie I (Wermeruv syndrom) - formy klinické manifestace: 5 kazuistik.

Multiple Endocrine Neoplasia (MEN) is a condition in which several endocrine organs of an individual are affected by adenoma, hyperplasia and less often carcinoma, either simultaneously or at different stages of life. Two existing syndromes, MEN1 and MEN2 (2A, 2B), in literature is also mentioned MEN4, are associated also with other non-endocrine disorders. MEN1 (Wermer syndrome) affects the pituitary, parathyroid, and pancreatic area. 95 % of patients show very early manifestation of hyperparathyroidism, often before 40 years of age. Multiple adenomas gradually involve all four parathyroid glands. The first clinical sign of MEN1 includes recurrent nephrolithiasis. The second most frequent manifestation of MEN1 is pancreatic area (pancreas, stomach and duodenum), again multiple malignancies of varying degree which can metastasize. Most often gastrinomas and insulinomas are involved. Pituitary adenomas occur in about one third of MEN1 patients and tend to be larger and less responsive to treatment. Tumors appearing most often are prolactinomas, tumors producing growth hormone, or afunctional adenomas. The other endocrine tumors include carcinoids and adrenal lesions. In the last year we have registered four MEN1 syndrome patients in our center and one patient has been already followed since 2008. In four out of five patients, nephrolithiasis after 30 years of age was the first clinical symptom, but only one of theses cases resulted in MEN1 diagnosis. In all patients, the clinical symptoms intensified and the diagnosis was established between 36 and 40 years of age. A crutial factor is a cooperation with the urology examination of kidney stones formation in young individuals with nephrolithiasis in order to reveal the potential cases of MEN1 syndrome very early on. Consider the MEN1 genetic diagnostics if recurrent primary hyperparathyroidism or recurrent gastroduodenal ulcer disease appear in patients under 40 years of age.Key words: carcinoid - gastrinoma - hyperparathyroidism - insulinoma - MEN1 - multiple endocrine neoplasia - nefrolithiasis - neuroendocrine tumor - pancreatic area - pituitary gland.

Ectopic insulin secreting neuroendocrine tumor of kidney with recurrent hypoglycemia: a diagnostic dilemma.

BACKGROUND: Hypoglycemia secondary to ectopic insulin secretion of non-pancreatic tumors is rare. CASE PRESENTATION: We describe a middle aged woman with recurrent hypoglycemia. On evaluation, she was detected to have hyperinsulinemic hypoglycemia and right sided renal mass lesion. 68Ga-Dotanoc and 99mTc-HYNICTOC scans confirmed the intrarenal mass to be of neuroendocrine origin. Right nephrectomy was done and it turned out to be an insulin secreting neuroendocrine tumour. Neuroendocrine nature of this tumour was further confirmed by ultra-structural examination. Her hypoglycemia did not recur after resection of this tumour. CONCLUSION: Few cases of ectopic insulin secretion have been reported though some are not proven convincingly. This case addresses all the issues raised in previous case reports and proves by clinical, laboratory, functional imaging and immunohistochemical analysis that ectopic origin of insulin by non-pancreatic tumors does occur. To our knowledge, this is the first reported case of ectopic insulinoma arising from the kidney.

A novel menin gene deletional mutation in a little series of Italian patients affected by apparently sporadic multiple endocrine neoplasia type 1 syndrome.

AIM: To perform a genetic screening for the multiple endocrine neoplasia type 1 (MEN1) gene mutations in patients affected by an apparently sporadic form of the disease, referred to an internal medicine unit of a large general hospital. SUBJECTS AND METHODS: In a group of 12 consecutive patients presenting clinical features of MEN type 1 syndrome, we performed a genetic screening for germline MEN1 gene mutations, including complete sequencing of the coding region (exons 2 to 10) and multiplex ligation-dependent probe amplification analysis for large deletion detection. RESULTS: Among these patients affected by apparently sporadic MEN type 1 syndrome, a targeted clinical history could detect indirect support for a diagnosis of familial condition only in 2 cases. The genetic screening identified pathogenic germline MEN1 gene mutations in 3 patients (25%). A previously unknown 18 base-pair deletion within exon 3, c.564_581delCAATGGGGAGCAGACAGC, resulting in loss of 6 amino acids (pAsp189_Ala194del), was found in heterozygosis in a woman affected by primary hyperparathyroidism and multifocal pancreatic neoplasia. CONCLUSIONS: Our results underscore the importance of performing genetic testing also in apparently sporadic MEN1 patients and extend the list of molecular variants leading to inactivation of the MEN1 gene.

Clinical features of insulinoma in patients with multiple endocrine neoplasia type 1: analysis of the database of the MEN Consortium of Japan.

More than 50% of patients with multiple endocrine neoplasia type 1 (MEN1) develop gastroenteropancreatic neuroendocrine tumors (GEPNETs), and insulinoma is the second most common functioning GEPNET. Compared to other functioning and nonfunctioning GEPNETs in MEN1, insulinoma is considered to develop at a younger age. To clarify the clinical features of insulinoma developed in Japanese patients with MEN1, a recently constructed database of Japanese MEN1 patients was analyzed. Among 560 registered cases, insulinoma was seen in 69 patients and information on age at diagnosis was available for 54 patients. Tumors predominantly occurred in the body and tail of the pancreas. The mean age at diagnosis of insulinoma (34.8 ± 16.7 yrs) was significantly younger than that of gastrinoma (50.6 ± 14.3 yrs) and nonfunctioning tumor (44.7 ± 13.3 yrs) in patients with MEN1. Patients diagnosed as having insulinoma during middle-age (30 - 49 yrs) tended to have a long period from appearance of hypoglycemic symptoms to diagnosis of the tumor. Of note, 13 patients (24%) were diagnosed as having insulinoma before 20 yrs of age. Such young onset was not seen in other GEPNETs. Since the development of GEPNETs during adolescence is quite rare, insulinoma diagnosed before 20 yrs strongly suggests the presence of MEN1 and warrants further investigation, including MEN1 genetic testing. Also, clinicians should be aware that insulinoma can often be missed in middle-aged patients.

Endocrine symptoms as the initial manifestation of Wilson's disease.

Wilson's disease is a rare genetic disorder of copper metabolism. The difference in copper tissue accumulation is responsible for the various clinical manifestations of this disorder. If left untreated, Wilson's disease progresses to hepatic failure, severe neurological disability, and even death. Due to the complex clinical picture of Wilson's disease, its diagnosis relies on a high index of suspicion. In our paper, we present endocrine symptoms suggesting the presence of insulinoma and hyperprolactinemia as the initial clinical manifestation of Wilson's disease in a young female. Zinc acetate treatment resulted in the disappearance of hypoglycemia, galactorrhea, and menstrual abnormalities.

Insulinoma in tuberous sclerosis: An entity not to be missed.

Pancreatic neuroendocrine tumors are rare with an incident rate of 5 cases per million individuals. Tuberous sclerosis complex is an autosomal dominant disease. This disease involves multisystem and occurs in one out of every 6,000-10,000 individuals. In this study, we describe a 47-year-old male known tuberous sclerosis patient with an insulinoma. The tumor was incidentally detected in follow-up imaging for a previous ampulla of Vater tubular adenoma. However, the patient reported symptoms of hypoglycemia. The insulinoma was enucleated successfully. Histopathology revealed a well-differentiated, grade one neuroendocrine tumor measuring around 2 cm in diameter. Seven cases were reported in the literature of tuberous sclerosis-associated insulinoma. The 7 reported cases had different hypoglycemia related symptoms. The reported tumors varied in size and location on the pancreas. This paper details the eighth case worldwide where an insulinoma occurred in a tuberous sclerosis patient.

[Endocrinological disorders in due to diseases of the pancreas]. / Zaburzenia wewnatrzwydzielnicze w przebiegu chorób trzustki.

During diseases of the pancreas not only extrasecretory but also intrasecretory disorders are observed. The disturbances are dependent on excessive or insufficient releasing of hormones which are physiologically secreted by the pancreas. The most common endocrine disorder, which develops in pancreatic diseases, is insufficient insulin production which leads to carbohydrates balance disorders. The occurrence of endocrine pancreatic tumors (insulinoma, gastrinoma) is visibly less common--2-10% of neoplasmy of the organ. In group of endocrine tumors of the pancreas are also observed some changes which are able to release the vase-active intestinal peptide (VIP-oma), glucagon tumors, carcinoid released serotonine and somatostatinoma. More over, low-differentiated endocrine carcinomas of the pancreas consist about 1% of all pancreatic tumors and 2-3% of the all endocrine tumors.

CD36 dependent redoxosomes promotes ceramide-mediated pancreatic ß-cell failure via p66Shc activation.

Altered metabolism is implicated in the pathogenesis of beta-cell failure in type 2 diabetes (T2D). Plasma and tissue levels of ceramide species play positive roles in inflammatory and oxidative stress responses in T2D. However, oxidative targets and mechanisms underlying ceramide signaling are unclear. We investigated the role of CD36-dependent redoxosome (redox-active endosome), a membrane-based signaling agent, in ceramide-induced beta-cell dysfunction and failure. Exposure of beta cells to C2-ceramide (N-acetyl-sphingosine) induced a CD36-dependent non-receptor tyrosine kinase Src-mediated redoxosome (Vav2-Rac1-NOX) formation. Activated Rac1-GTP-NADPH oxidase complex induced c-Jun-N-terminal kinase (JNK) activation and nuclear factor (NF)-kB transcription, which was associated with thioredoxin-interacting protein (TXNIP) upregulation and thioredoxin activity suppression. Upregulated JNK expression induced p66Shc serine36 phosphorylation and peroxiredoxin-3 hyperoxidation, causing beta-cell apoptosis via mitochondrial dysfunction. CD36 inhibition by sulfo-N-succinimidyl oleate (SSO) or CD36 siRNA blocked C2-ceramide-induced redoxosome activation, thereby decreasing JNK-dependent p66Shc serine36 phosphorylation. CD36 inhibition downregulated TXNIP expression and promoted thioredoxin activity via enhanced thioredoxin reductase activity, which prevented peroxiredoxin-3 oxidation. CD36 inhibition potentiated glucose-stimulated insulin secretion and prevented beta-cell apoptosis. Our results reveal a new role of CD36 during early molecular events that lead to Src-mediated redoxosome activation, which contributes to ceramide-induced pancreatic beta-cell dysfunction and failure.

Maternal resistin predisposes offspring to hypothalamic inflammation and body weight gain.

Resistin promotes hypothalamic neuroinflammation and insulin resistance through Toll like receptor 4 (TLR4), this hormone is thought to be a link between obesity and insulin-resistance. Indeed, resistin plasma levels are higher in obese and insulin resistant subjects. However, the impact of maternal resistin on the predisposition of offspring to hypothalamic neuroinflammation is unknown. Here, female mice were treated with resistin during gestation/lactation periods, then hypothalamic neuroinflammation was investigated in male offspring at p28 and p90. At p28, resistin increased the expression of inflammation markers (IL6, TNFα and NFκB) and TLR4 in the hypothalamus and decreased both hypothalamic insulin and leptin receptors' expression. The hypothalamic up-regulation IL6, TNFα and TLR4 was sustained until p90 promoting most likely hypothalamic inflammation. Maternal resistin also increased IL6 and TNFα in the adipose tissue of offspring at p90 associated with a higher body weight gain. In contrast, liver and muscle were not affected. These findings reveal that the augmentation of maternal resistin during gestation and lactation promotes hypothalamic and adipose tissue inflammation of offspring as evidenced by sustained increase of inflammation markers from weaning to adulthood. Thus, maternal resistin programs offspring hypothalamic and adipose tissue inflammation predisposing then offspring to body weight gain.

Insulinoma and gastrinoma syndromes from a single intrapancreatic neuroendocrine tumor.

CONTEXT: The insulinoma syndrome is marked by fasting hypoglycemia and inappropriate elevations of insulin. The gastrinoma syndrome is characterized by hypergastrinemia, ulcer disease, and/or diarrhea. Rarely, insulinoma and gastrinoma coexist in the same patient simultaneously. OBJECTIVE: Our objective was to determine the cause of a patient's hypoglycemic episodes and peptic ulcer disease. DESIGN AND SETTING: This is a clinical case report from the Clinical Research Center of the National Institutes of Health. PATIENT AND INTERVENTION: One patient with hypoglycemic episodes and peptic ulcer disease had a surgical resection of neuroendocrine tumor. RESULTS: The patient was found to have a single tumor cosecreting both insulin and gastrin. Resection of this single tumor was curative. CONCLUSIONS: A single pancreatic neuroendocrine tumor may lead to the expression of both the hyperinsulinemic and hypergastrinemic syndromes.

The induction of insulinomas by X-irradiation to the gastric region in Otsuka Long-Evans Tokushima Fatty rats.

The X-ray induction of tumors was examined in five-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, treated with two 10 Gy doses to the gastric region with a 3-day interval (total 20 Gy). After irradiation, the rats received the commercial diet MF and tap water and were maintained for up to 564 days. The mean serum glucose level in the X-irradiated group was significantly lower than that in the non-irradiated animals at the 18 month time point. The total tumor incidence was 27/30 (87.1%) in the treated rats (islet tumors, gastric tumors, sarcomas, seminomas, adrenal tumors, kidney tumors, papilloma, lymphomas and mammary tumors). Islet tumors, generally showed to be positive for insulin by immunohistochemistry, developed in 19 rats (63.3%), and were associated with low serum glucose. Since spontaneous tumors observed in 6/19 (31.6%) rats (sarcomas, kidney tumors, duodenum tumors, seminoma, adrenal tumor and squamous cell carcinoma) did not include any insulinomas, these are clearly induced by X-irradiation in OLETF rats.

Delayed Imaging Presentation of a Symptomatic Insulinoma After Bariatric Surgery.

Many reports exist on hyperinsulinemic hypoglycemia after bariatric surgery, which can result in persistence of the metabolic syndrome in patients who have undergone these procedures. While the noninsulinoma pancreatogenous hypoglycemia syndrome, or nesidioblastosis, has garnered increased attention in these patients, its presentation is similar to patients with an insulinoma and this entity must therefore be evaluated and ruled out. Herein, we present a patient who developed symptoms of hypoglycemia 7 years after Roux-en-Y gastric bypass surgery. While a diagnosis of insulinoma was entertained, his laboratory values were indeterminate and imaging localization was inconclusive. Because of significant medical comorbidities, he was managed symptomatically until imaging ultimately localized a lesion in the pancreatic uncinate process consistent with an insulinoma. He subsequently underwent resection and remains disease and symptom free 1 year after surgery. This case demonstrates the diagnostic and imaging dilemma in patients with hypoglycemia after bariatric surgery and should be of interest to anyone who cares for these patients.

Pancreatic endocrine tumors are a rare manifestation of the neurofibromatosis type 1 phenotype: molecular analysis of a malignant insulinoma in a NF-1 patient.

The tumorigenesis of sporadic endocrine tumors is still not fully understood. It is well known that patients with von Recklinghausen syndrome (NF-1) (OMIM 162200) carrying NF1 germline mutations are predisposed to endocrine tumors including pheochromocytomas and duodenal somatostatinomas. It is unclear, however, whether the rarely reported occurrence of pancreatic insulinomas in NF-1 patients represents a coincidental finding or whether insulinomas are a rare manifestation of the NF-1 syndrome. To determine the potential association between the NF-1 syndrome and pancreatic endocrine tumors, we analyzed a NF-1 patient with a well-differentiated pancreatic endocrine carcinoma for NF1 mutation, allelic loss of the NF1 gene and its expression in peripheral blood and tumor cells. The germline mutation c. 499 del TGTT known in the family was confirmed by polymerase chain reaction (PCR) and direct sequencing of exon 4 in DNA extracted from peripheral blood. Loss of heterozygosity (LOH) analysis of the NF1 gene was carried out using 3 intragenic microsatellite markers on 17q11.2. RNA expression was examined by reverse transcription and a consecutive PCR spanning intron 3 of the NF1 gene including the mutated site in exon 4. Immunohistochemistry was used to analyze NF-1 protein expression. Mutation analysis of peripheral blood leukocytes confirmed the 4 base pair deletion in exon 4 starting at codon 167 (499 del TGTT). LOH analysis of tumor tissue revealed retention of both NF1 alleles. While reverse transcriptase-PCR of peripheral blood showed bi-allelic expression of both the wild-type NF1 and the mutated form, reverse transcriptase-PCR of tumor extracts demonstrated expression of the mutated but not the wild-type NF1 allele. Additionally, neurofibromin, the NF1 gene product, was absent in the tumor tissue of the NF-1 patient. These results show that the wild-type NF1 transcrips and protein are reduced, in the reported insulinoma, supposedly by epigenetic mechanisms. This provides strong evidence that there is a relationship between von Recklinghausen disease and the patient's insulinoma. In this line, insulinomas may be viewed as a rare manifestation of the NF-1 syndrome. Furthermore, the NF1 gene must be considered as a candidate tumor suppressor gene for sporadic insulinomas and probably other pancreatic endocrine tumors.

Pancreatic beta-cell-specific ablation of the multiple endocrine neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice.

The function of the predisposition gene to multiple endocrine neoplasia type 1 (MEN1) syndrome remains largely unknown. Previous studies demonstrated that null mutation of the Men1 gene caused mid-gestation lethality in mice, whereas heterozygous Men1 knockout mice developed multiple endocrine tumors late in life. To seek direct evidence on the causal role of menin in suppressing tumor development, we generated mice in which the Men1 gene was disrupted specifically in pancreatic beta cells. These mice began to develop hyperplastic islets at as early as 2 months of age and insulinomas at 6 months of age. The islet lesions exhibited features of multistage tumor progression, including beta-cell dedifferentiation, angiogenesis, and altered expression of both E-cadherin and beta-catenin. Additionally, disturbance of blood insulin and glucose levels correlated with tumor development, mimicking human MEN1 symptoms. Our data indicate that this strain of mice provides a powerful tool for the study of the mechanisms of tumorigenesis related to MEN1 disease.

Inhibitory effect of streptozotocin on tumor development in transgenic mice bearing an elastase I-SV40 T-antigen fusion gene.

Transgenic mice, bearing a fusion gene of rat elastase I promoter and SV40 T-antigen, developed acinar cell tumors of the pancreas, as predicted by the model. In addition, they developed insulinomas and somatostatin (delta)-cell hyperplasia of the pancreatic islets. The insulinomas and the delta-cell hyperplasia appeared to be functional, as evidenced by changes in plasma glucose, insulin, and somatostatin. Streptozotocin, which has been shown to inhibit pancreatic carcinogenesis in the hamster model, significantly reduced the numbers of insulinomas and delta-cell hyperplasias. Streptozotocin did not cause a statistically significant reduction in exocrine tumors.

Surgical strategy for insulinomas in multiple endocrine neoplasia type I.

BACKGROUND: Hyperinsulinemia in multiple endocrine neoplasia type I (MEN-I) is a rare but potentially curable condition that presents difficulties not encountered in sporadic cases. METHODS: The present report documents our surgical approach to 3 MEN-I patients with hyperinsulinemia. RESULTS: Primary hyperparathyroidism was manifested in all 3 patients at the time of presentation. Distal subtotal pancreatectomy with enucleation of tumor at the head of pancreas detected intraoperatively resulted in immediate cure of 2 patients. Persistent disease occurred in 1 patient after enucleation of tumor at the head of the pancreas guided by preoperative imaging elsewhere. The patient was subsequently cured by distal subtotal pancreatectomy. Pathology revealed multiple tumors (4 to 14) in all patients. CONCLUSIONS: A different surgical strategy with an aim of distal subtotal pancreatectomy and enucleation of any tumor identified in the head of pancreas is the treatment of choice for hyperinsulinemia in MEN-I patients.