Multiple Endocrine Neoplasia Syndrome Type Research Articles

Clinical characterization of a cohort of patients with multiple endocrine neoplasia syndrome type 1 (MEN1): role of the MEN1 gene mutation on the phenotypic expression of the syndrome

Clinical characterization of a cohort of patients with multiple endocrine neoplasia syndrome type 1 (MEN1): role of the MEN1 gene mutation on the phenotypic expression of the syndrome

Clinical Activity of Selpercatinib in RET-mutant Pheochromocytoma.

Activating RET alterations have been reported in a variety of solid tumors, including pheochromocytoma where they occur both sporadically and as part of familial multiple endocrine neoplasia type 2 (MEN2) syndromes. Selpercatinib is a first-in-class, highly selective, and potent small molecule RET kinase inhibitor that has demonstrated marked and durable anti-tumor activity in diverse RET-activated solid tumors in the LIBRETTO-001 study (NCT03157128). We describe the first six pheochromocytoma cases treated with selpercatinib in the LIBRETTO-001 study. Of the six patients (one sporadic and five reported as part of MEN2 syndromes) in this case report, four had a partial response/complete response and two had stable disease per independent review committee. Treatment duration ranged from 9.2 months to more than 56.4 months. The safety profile of treatment was consistent with selpercatinib in other indications. These data support selpercatinib as an effective therapy against RET-mutant pheochromocytoma, adding to the diversity of RET-activated tumor types that may benefit from targeted RET inhibition.

A cohort study of CNS tumors in Multiple Endocrine Neoplasia Type 1.

Multiple Endocrine Neoplasia Type-1 (MEN1) is thought to increase the risk of meningioma and ependymoma. Hereby, we aimed to describe the frequency, the incidence and specific clinical and histological features of CNS tumors in the MEN1 population (except pituitary tumors). The study population included patients harboring CNS tumors diagnosed with MEN1 syndrome after 1990 and followed-up in the French MEN1 national cohort. Standardized incidence rate (SIR) was calculated based on the French Gironde CNS tumors registry. Genomic analyses were performed on somatic DNA from 7 CNS tumors including meningiomas and ependymomas from MEN1 patients, then in 50 sporadic meningiomas and ependymomas. Twenty-nine CNS tumors were found among the 1498 symptomatic patients (2%) (incidence=47.4/100'000 person-years; SIR=4.5), including 12 meningiomas (0.8%) (incidence=16.2/100'000; SIR=2.5), 8 ependymomas (0.5%) (incidence=10.8/100'000; SIR=17.6), 5 astrocytomas (0.3%) (incidence=6.7/100'000; SIR=5.8), and 4 schwannomas (0.3%) (incidence=5.4/100'000; SIR=12.7). Meningiomas in MEN1 patients were benign, mostly meningothelial, with 11 years earlier onset compared to the sporadic population and an F/M ratio of 1/1. Spinal and cranial ependymomas were mostly classified WHO grade 2. A biallelic MEN1 inactivation was observed in 4/5 ependymomas and 1/2 meningiomas from the MEN1 patients, whereas MEN1 deletion in one allele was present in respectively 3/41 and 0/9 sporadic meningiomas and ependymomas. Incidence of each CNS tumor was higher in the MEN1 population than in the French general population. Meningiomas and ependymomas should be considered part of the MEN1 syndrome, but somatic molecular data are missing to conclude for astrocytomas and schwannomas.

P-43 Pancreatic insulinoma with delayed challenging diagnosis by 68Ga-DOTATATE PET/CT scan: Case report

Abstract Introduction Insulinoma (I) is most common neuroendocrine pancreatic tumor with an incidence of 0.1-0.3/100000(1). It is faintly more in females and can develop at any age(2). Usually benign, sporadic, less than 2 cm, solitary and in 10% of cases is multiple and happens as a component of multiple endocrine neoplasia syndrome type I (MEN–I)(3). Nonspecific symptoms may lead to delayed or misdiagnosis. Improper insulin secretion causes clinical features of hypoglycemia(2). Laboratory verification, localization followed by surgical removal are the main steps management. Localization may be difficult and delayed as here. Clinical Case A female of 58 years old with episodes of sweating, palpitation and tremor improved by drinking sweets, weight gain and denied any drugs intake. No personal or family history of diabetes or antidiabetic drugs. Body weight was 87 kg. Investigations during the attack showed low plasma glucose of 36 mg/dL, high serum insulin of 94.8 mIU/L (1.7 - 31), elevated C-peptide of 10.6 ng/mL (0.9-4). Cortisol and thyroid function are normal. Abdominal ultrasound (US), CT scan and MRI are normal. Due to failure of localization of Insulinoma, treatment by diazoxide started with no response. Octreotide long-acting repeatable (Octreotide LAR) 20 mg monthly injection was initiated and increased to 30 mg monthly with good improvement and less attacks. After three years, the patient developed abdominal pain and abdominal US showed multiple gall stones. The patient was advised to do 68Ga-DOTATATE PET/CT Scan, which revealed distal pancreatic mass of 26 mm (Figure1A and B). Distal pancreatectomy and cholecystectomy had been done with smooth postoperative period normal normal plasma glucose, insulin and c-peptide with no further hypoglycemia, histopathological examination confirmed Insulinoma (Figure 2A and B). Hypoglycemic symptoms of I, whether neuroglycopenic or sympathoadrenal are precipitated by fasting or exercise and could precede diagnosis by months and even years(3). Insulinoma, should be suggested when patient has typical Whipple's triad, high insulin, c-peptide and proinsulin during the attack(3). Weight gain noted in about 18% of cases(4). Modalities used to localize Insulinoma include trans-abdominal US, CT scan, MRI, EUS (endoscopic ultrasound), intraoperative US, intraoperative palpation and arteriography. An American study considered 68Ga-DOTATATE PET/CT as an adjuvant tool for diagnosis with 90% detection rate (5). A 90-95% of cases are benign, patients have high survival with complete resolution of symptoms after excision with only 5.4% recurrences(6). Malignant I limited to pancreas and responsive to chemotherapy has 5 years survival rate after resection and 19 months for recurrent tumors(6). Conclusion Insulinoma should be considered in patients with typical clinical and laboratory finding. Follow up, assessment and different imaging techniques are main steps in management with teamwork.Figure 1.68Ga-DOTATATE PET/CT Scan68Ga-DOTATATE PET/CT Scan revealed distal pancreatic mass of 26 mm

O-05 A novel mutation of MEN1 gene in familial Multiple Endocrine Neoplasia Type 1 (MEN1): A report of two cases

Abstract Introduction Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare (1-9/100000) autosomal dominant disease. It is characterized by primary hyperparathyroidism (90%), enteropancreatic tumor (60-70%), non-functional adrenal adenomas (30%) and pituitary tumors (10-20%). Herein, we present two cases in the same family with MEN1 syndrome caused by a novel mutation. Clinical Case 1: 49-year-old male presented to our clinic with fasting hypoglycemia. Fasting serum glucose (FSG) was 51 mg/dl and serum cortisol was 18 ug/dl. During the hypoglycemia in prolonged fasting test, the serum levels of glucose, insulin and C-peptide were 37 mg/dl, 17.3 mu/l, 7.75 ng/ml respectively (Table 1). Abdominal MRI revealed mass lesions in the pancreas (Figure 1). Ultrasonography of the neck and MIBI scintigraphy performed because of the high levels of calcium and parathyroid hormone (PTH), were consistent with parathyroid adenoma (Table 2). Pituitary MRI showed a 12 mm macroadenoma. He underwent parathyroidectomy and distal pancreatectomy simultaneously. The resected specimens revealed a well-differentiated neuroendocrine tumor (NET) of the pancreas and parathyroid adenoma. The patient had no new hypoglycemic episodes after surgery and serum calcium remained within the normal range (Table 2). Central hypothyroidism and hypogonadotropic hypogonadism which was resulted from the pressure of the adenoma was managed medically. Genetic testing revealed a heterozygous mutation in NM_001370251.1:c.949del(HET). First degree relatives of the patient were screened for MEN. Clinical Case 2: The son of case 1, an 18-year-old male, presented with fasting hypoglycemia. He had a BMI of 37 kg/m2 and underwent gastric botox 3 months prior to his presentation. FPG was 52 mg/dl and serum cortisol was 20 ug/dl. Prolonged fasting test confirmed the diagnosis of insulinoma (Table 1). Abdominal MRI showed a pancreatic tail mass 37×22 mm in size. Gallium 68 PET/CT DOTATATE revealed increased uptake in multiple lesions in the pancreas. Ultrasonography and MIBI scintigraphy showed a parathyroid adenoma. A nonfunctional microadenoma was detected in pituitary MRI. The patient underwent distal pancreatectomy. Following pancreatectomy, right superior and left inferior parathyroidectomies were performed. Since his serum calcium levels started to increase in 48 hours after the operation, the patient has had second operation for left superior parathyroidectomy. After the operation, the serum calcium and parathyroid hormone levels were 9.2 mg/dl, 58 pg/ml respectively. Specimens revealed well-differentiated NET and atypical parathyroid adenoma. The patient was found to have the same genetic mutation with his father and during the follow up the serum glucose and calcium levels remained within the normal range (Table 2). Conclusion In the genetic examination the heterozygous mutation NM_001370251.1:c.949del(HET) in exon 7/11 of the MEN1 gene found in our patients represents a novel mutation.Figure 1.MRI showing pancreatic masses  Table 1.Laboratory findings  Table 2.Prolonged fasting test

Innovations in the systemic treatment of medullary thyroid cancer with kinase inhibitors

Introduction: Medullary thyroid carcinoma is a primary thyroid neoplasm originating from thyroid C cells. It can be familial or sporadic. The familial form is associated with multiple endocrine neoplasia (MEN) syndrome types 2A and 2B and is caused by a mutation in the RET gene, which encodes a tyrosine kinase receptor. Treatment of medullary thyroid cancer is mainly based on surgical resection of the thyroid gland, usually a total thyroidectomy. It can be followed-up by a chemotherapy, which has limited efficacy. Hence, there is a growing interest in new molecular therapies, such as tyrosine kinase inhibitors, which include vandetanib, cabozantinib, selpercatinib, pralsetinib, sorafenib and lenvatinib.
 Objective: The review and presentation of the current state of knowledge on the systemic treatment of medullary thyroid cancer with kinase inhibitors.
 Material and methods: Literature review based on available sources from PubMed database and Google Scholar.
 Conclusions: Though systemic treatment options for medullary thyroid cancer continue to improve, patients with advanced neoplasms still have limited therapeutic options. Hence, further development of targeted treatment with kinase inhibitors, particularly those selective for the RET receptor is crucial. Molecular studies of mutations and signaling pathways involved in the oncopathogenesis of medullary thyroid cancer could contribute to the discovery of new therapeutic mechanisms, and drugs that target them, could potentially further improve disease progression-free survival (PFS) and overall survival (OS).

Recurrent Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 1 Syndrome.

Primary hyperparathyroidism is a common endocrinopathy. Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare autosomal dominantly inherited endocrine tumor predisposition syndrome, with one of main manifestations being primary hyperparathyroidism. We retrospectively evaluated a set of 1011 patients who underwent surgery for primary hyperparathyroidism between the years 2018-2022, and found 78 (8 %) patients who underwent reoperations and 27 patients with MEN1 syndrome. In the group of patients with MEN1 syndrome, 7 (35 %) needed reoperations. Patients with multiple endocrine neoplasia syndrome have a higher risk of needing reoperation. Genetic testing can help identify MEN1 syndrome preoperatively and to better evaluate the approach to surgery.

SAT309 Clinical And Genetic Profiling Of Patients With Multiple Endocrine Neoplasia Type 2 Syndrome And Screening for Medullary Thyroid Carcinoma In Asymptomatic First-degree Relatives

Abstract Disclosure: K. Kumar P: None. Y. Gupta: None. A. Goyal: None. D. Kandasamy: None. N. Tandon: None. Background: Multiple endocrine neoplasia type 2 (MEN2) syndrome is a rare disorder with autosomal dominant inheritance, characterised by the presence of two of the following three endocrine manifestations: medullary thyroid carcinoma (MTC), pheochromocytoma (PCC) and primary hyperparathyroidism (PHPT) [1-2]. There is a paucity of data on clinical and genetic profile of MEN2 syndrome in the Indian subcontinent. Objectives: We aimed to evaluate the clinical and genetic profile of patients with MEN2 syndrome and perform screening for MTC among asymptomatic family members with serum calcitonin. Materials and Methods: This was an ambispective study conducted in the Department of Endocrinology at AIIMS New Delhi, involving diagnosed patients of MEN2 syndrome between January 2016 and December 2022. Results: We evaluated a total of 24 families with MEN2 syndrome comprising 61(MEN2A, n=56; MEN2B, n=5) patients, 18 patients were diagnosed as index cases. Data were derived retrospectively for 46 patients (MEN2A, n=43 MEN2B, n=3) and prospectively for 15 patients (MEN2A, n=13; MEN2B, n=2). The mean age at presentation of MEN2A and MEN2B were 28.6 ± 13.52 years and 22 ± 4.44 years, respectively. Of the study patients, 35 (57.38%) were females, among them 32 were MEN2A. Among 18 index patients 67% were synchronously detected to have MTC and PCC while 33% had MTC preceding PCC. Among patients with MEN2A syndrome 33 (59%) had MTC, 21(38%) had simultaneous PCC and MTC and one patient had PCC as presentation. We noted PHPT in 5 (9%) patients with MEN2A syndrome. Of the 5 patients with MEN2B syndrome, 4 (80%) presented with synchronous MTC and PCC and one (20%) presented with MTC aloneMetastatic MTC was noted in six patients with MEN2A syndrome and two patients with MEN2B syndrome. Median baseline Sr calcitonin level was 42 (4-1721) pg./ml in non-Metastatic group vs 3945(928-35572) pg./ml in distant metastasis group. 1 patient had metastasis from PCC to liver. Mutational analysis data are available for 40 patients. The most common mutations in MEN2A and MEN2B groups were C634R (exon 11 of RET gene, n=21) and M918T (exon 16 of RET gene, n=4), respectively.A total of 177 eligible family members of index patients with MEN2A syndrome were contacted, of whom 83 turned up for screening and 42 (50.6%) had elevated serum calcitonin levels (>10 pg./ml). Of the 26 eligible family members of index patients with MEN2B syndrome, only 9 could be screened and all had normal serum calcitonin levels (<10 pg./ml). Discussion & Conclusion: 1) This is the largest study comprising 61 patients after screening 24 family members in India. 2) Synchronous presentation of MEN2 with PCC and MTC is 67% vs 17% in western literature in Index patients. 3) MEN2 syndrome should be suspected in patients with MTC and young-onset PCC and all first-degree relatives of index patients with this syndrome. Presentation: Saturday, June 17, 2023

Medullary thyroid cancer: epidemiology

Epidemiology of medullary thyroid cancer is presented in the literature review. Thyroid cancer is the most common form of endocrine oncological pathology. It accounts for 96–97 % of all malignant tumors of endocrine organs. According to the Surveillance, Epidemiology, and End Results Program (USA), the incidence of thyroid cancer in 1975–2009 increased approximately threefold, from 4.9 to 14.3 cases per 100,000 population. At the same time, the mortality rate remained low, approximately at the same level, 0.5 cases per 100,000. Such a situation can be explained to some extent by the improvement of diagnostic capabilities of the early, often preclinical, stage of thyroid tumors. Medullary thyroid cancer ranks third after papillary and follicular cancer, but surpasses them in terms of aggressiveness. It is a re­latively rare disease. This type of tumor makes up 1–9 % of all thyroid cancers. Against the background of the general tendency to increase the incidence of thyroid cancer, the absolute number of cases of medullary cancer according to various data remains relatively stable. Epidemiological characteristics of medullary thyroid cancer deserve attention in the age aspect, as well as when considering the frequency of detecting these tumors at autopsy of people who had no signs during their lifetime. In clinical practice, medullary thyroid cancer occurs in two main forms — sporadic and hereditary. The latter is represented as part of the combined syndrome of multiple endocrine neoplasia type 2 (MEN-2), which, in turn, is divided into two subtypes: MEN-2A and MEN-2B syndromes. MEN-2 syndrome is a rare combined hereditary pathology. Sporadic medullary thyroid cancer accounts for approximately 70–80 % of such tumors. It is accompanied by other types of endocrinopathies. Most cases of medullary thyroid cancer occur in the fifth decade of life. The presented data on the epidemiology of medullary thyroid cancer allow for a more detailed and in-depth study of this pathology and contain a certain amount of useful and necessary information.

Differences in clinical characteristics, treatment, and outcomes of sporadic and MEN-1-related insulinomas.

Although in most cases insulinomas are small, benign, sporadic tumours, they can also be associated with hereditary syndromes, most commonly multiple endocrine neoplasia type 1 (MEN-1). Such a diagnosis significantly affects patient management. The objective was to elucidate the clinical differences between sporadic and MEN-1-linked insulinoma. Comparison of clinical and histopathological characteristics, types of surgery, and outcomes of patients with sporadic and MEN-1-related insulinoma diagnosed between 2015 and 2022. There were 17 cases of insulinomas that underwent MEN-1 genetic testing (10 women and 7 men). In 7 cases, the mutation in the menin gene was confirmed. The median age at the time of diagnosis of sporadic insulinoma related to MEN-1 was 69 years (range 29-87) and 31.5 years (16-47), respectively. Primary hyperparathyroidism (PHP) was found in 6 of 7 patients with MEN-1-related insulinoma, while in none of the patients without MEN-1 mutations. Multifocal pancreatic NETs were found in 3 patients with MEN-1 syndrome, while in all sporadic cases there was a single pancreatic tumour. Two patients with insulinoma related to MEN-1 had a positive familial history of MEN-1-related diseases, while none with sporadic form. Dissemination at diagnosis was found in 4 cases, including 3 patients with insulinoma related to MEN-1-related insulinoma. Patients with sporadic and MEN-1-related insulinoma did not differ in tumour size, Ki-67 proliferation index, and outcome. Of all the features evaluated, only the multifocal nature of pancreatic neuroendocrine tumour (PanNET) lesions and a positive family history differentiated between patients with sporadic and MEN-1-related insulinomas. An age of insulinoma diagnosis of less than 30 years may be a strong indicator of an increased risk of MEN-1 syndrome.

Diagnostic Utility of Menin Immunohistochemistry in Patients With Multiple Endocrine Neoplasia Type 1 Syndrome.

A clinical diagnosis of multiple endocrine neoplasia type 1 (MEN1) syndrome is usually confirmed with genetic testing in the germline. It is expected that menin protein expression is lost in MEN1-related tumors. Therefore, we investigated the potential of menin immunohistochemistry in parathyroid adenomas as an additional tool in the recognition and genetic diagnosis of MEN1 syndrome. Local pathology archives were searched for parathyroid tumors from patients with MEN1 syndrome and without MEN1, including sporadic, patients with multiple endocrine neoplasia type 2A and hyperparathyroidism-jaw parathyroid tumors. Menin immunohistochemistry was performed and its use to identify MEN1-related tumors was assessed. Twenty-nine parathyroid tumors from 16 patients with MEN1 and 61 patients with parathyroid tumors from 32 non-MEN1 were evaluated. Immunohistochemical nuclear menin loss in one or more tumors was found in 100% of patients with MEN1 and 9% of patients with non-MEN1. In patients with multiple tumors, menin loss in at least one tumor was seen in 100% of 8 patients with MEN1 and 21% of patients with 14 non-MEN1. Using a cutoff of at least 2 tumors showing menin loss per patient, the positive and negative predictive values for the diagnosis MEN1 were both 100%. The practical and additional value of menin immunohistochemistry in clinical genetic MEN1 diagnosis is further illustrated by menin immunohistochemistry in 2 cases with a germline variant of unknown significance in the MEN1 gene. Menin immunohistochemistry is useful in the recognition of MEN1 syndrome as well as in the clinical genetic analysis of patients with inconclusive MEN1 germline testing.

A case of multiple endocrine neoplasia syndrome type 2A combined with autoimmune polyendocrine syndrome type Ⅲ

报道1例51岁女性患者，以阵发性头痛、心悸、大汗1年，腰背胀痛2周入院。检测血浆游离甲氧基肾上腺素、游离甲氧基去甲肾上腺素、降钙素明显升高；先后行双侧肾上腺占位及甲状腺结节手术，术后组织病理学诊断分别为嗜铬细胞瘤及甲状腺髓样癌，基因检测示RET基因11号外显子634密码子处基因点突变，考虑为多发性内分泌腺肿瘤综合征2A型。患者存在1型糖尿病及自身免疫性甲状腺炎，考虑为自身免疫性多内分泌腺病综合征Ⅲ型。.

Abstract #1412022: A Rare Case of Multiple Endocrine Neoplasia Type 1 (MEN1) Presenting with Recurrent Abdominal Pain

MEN1 is a rare genetic disorder characterized by combined occurrence of two or more tumors involving parathyroid, anterior pituitary and the neuroendocrine tissue of gastro-entero-pancreatic organ system. We present a case of a young male with recurrent abdominal pain who was later diagnosed with MEN1 syndrome. 27-year-old male with past medical history of chronic abdominal pain presented for an episode of acute upper abdominal pain which was constant and worsened with any movement or palpation. His family history was significant for father having parathyroid disorder and skin lesions. On examination, he was ill appearing with tachycardia, multiple skin lesions and tenderness in upper abdomen. Labs were significant for leukocytosis and hypercalcemia (corrected level 10.5 mg/dl). Rest of the electrolytes, kidney function, liver enzymes and lipase were normal. Computed tomography (CT) abdomen showed inflammatory changes and thickening along the distal stomach/proximal duodenum with scattered free air, concerning for a perforated ulcer. Indeterminate bilateral adrenal nodules were also noted. Patient underwent emergent exploratory laparotomy and was noted to have small perforation in the anterior proximal portion of the duodenum which was repaired. Post-operatively, work up for persistent hypercalcemia revealed parathyroid hormone levels of 152 pg/ml and 25-hydroxy vitamin D of 13.7 ng/ml. He was diagnosed with primary hyperparathyroidism and upon stabilization, discharged with plan for outpatient follow-up. After few months, he had another admission due to worsening epigastric pain. Repeat CT abdomen showed multiple pancreatic lesions involving head, tail and uncinate process and stable adrenal nodules. Presence of pancreatic lesions, gastric ulcers, hyperparathyroidism, adrenal nodules, and multiple skin lesions raised concern of MEN1. Further evaluation showed elevated gastrin level (633 pg/ml), chromogranin level (2464 ng/mL) and mildly elevated prolactin. Rest of pituitary and adrenal axis hormone levels were normal. MEN1 gene testing was positive. No pituitary lesion was identified on magnetic resonance imaging brain. He underwent subtotal parathyroidectomy and cervical thymectomy. He was continued on twice daily pantoprazole and was discharged home in stable condition. MEN1 tumor types and age of tumor onset can differ significantly, and tumors become evident either by hormonal overproduction or by tumor growth. There are no genotype phenotype correlations, even within the same family. Pharmacological therapies to suppress hypersecretion are often first line and can be successful in up to 50% patients. Surgery is an option for patients with hypersecretion unresponsive to medical therapy, compression of the optic nerves and/or chiasma endangering vision or when there is uncertainty of diagnosis requiring biopsy. MEN1 is linked with higher mortality. Approximately 70% of the MEN1 deaths are due to thymic neuroendocrine tumors (NETs) and duodenopancreatic-NETs. Early diagnosis of tumors with appropriate interventions can significantly improve patient survival.

Insulinoma in childhood: a retrospective review of 22 patients from one referral centre.

Insulinomas are very rare in childhood with sparse knowledge on the clinical aspects and the presence of Multiple Endocrine Neoplasia type 1 (MEN1). We conducted a retrospective review of patients diagnosed with insulinoma between 1995 and 2021, presenting to one referral centre in Russia. Clinical, biochemical, genetic, imaging and histological data were collected. In addition, follow-up and family data were obtained. A total of twenty-two children aged 5 to 16 years were identified. The median (range) gap between the first hypoglycaemia symptoms and diagnosis was 10 (1-46) months. Twelve children (55%) were misdiagnosed to have epilepsy and were treated with anticonvulsants before hypoglycemia was revealed. Contrast enhanced MRI and/or CT were accurate to localize the lesion in 82% (n=18). Five patients (23%) had multiple pancreatic lesions. All children underwent surgical treatment. The median (range) diameter of removed tumors was 1.5 (0.3-6) cm. Histopathological studies confirmed the presence of insulinoma in all cases. Immunohistochemical studies revealed G2 differentiation grade in 10 out of 17 cases. Two patients were diagnosed with metastatic insulinoma. One of them had metastases at the time of insulinoma diagnosis, while the other was diagnosed with liver metastases eight years after the surgery. Eight children (36%) were found to carry MEN1 mutations, inherited n=5, de novo n=1, no data, n=2. Children with MEN1 had significantly higher number of pancreatic tumors compared to sporadic cases. All of them developed additional MEN1 symptoms during the following 2-13 years. In the five patients with inherited MEN1, seven family members had hitherto undiscovered MEN1 manifestations. In this large cohort of children with rare pediatric insulinomas, MEN1 syndrome and G2 tumors were frequent, as well as hitherto undiscovered MEN1 manifestations in family members. Our data emphasize the need of genetic testing in all children with insulinoma and their relatives, even in the absence of any other features, as well as the importance of a prolonged follow-up observation.

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.

Approach of Multiple Endocrine Neoplasia Type 1 (MEN1) Syndrome-Related Skin Tumors.

Non-endocrine findings in patients with MEN1 (multiple endocrine neoplasia) syndrome also include skin lesions, especially tumor-type lesions. This is a narrative review of the English-language medical literature including original studies concerning MEN1 and dermatological issues (apart from dermatologic features of each endocrine tumor/neuroendocrine neoplasia), identified through a PubMed-based search (based on clinical relevance, with no timeline restriction or concern regarding the level of statistical significance). We identified 27 original studies involving clinical presentation of patients with MEN1 and cutaneous tumors; eight other original studies that also included the genetic background; and four additional original studies were included. The largest cohorts were from studies in Italy (N = 145 individuals), Spain (N = 90), the United States (N = 48 and N = 32), and Japan (N = 28). The age of patients varied from 18 to 76 years, with the majority of individuals in their forties. The most common cutaneous tumors are angiofibromas (AF), collagenomas (CG), and lipomas (L). Other lesions are atypical nevi, basocellular carcinoma, squamous cell carcinoma, acrochordons, papillomatosis confluens et reticularis, gingival papules, and cutaneous T-cell lymphoma of the eyelid. Non-tumor aspects are confetti-like hypopigmentation, café-au-lait macules, and gingival papules. MEN1 gene, respective menin involvement has also been found in melanomas, but the association with MEN1 remains debatable. Typically, cutaneous tumors (AF, CG, and L) are benign and are surgically treated only for cosmetic reasons. Some of them are reported as first presentation. Even though skin lesions are not pathognomonic, recognizing them plays an important role in early identification of MEN1 patients. Whether a subgroup of MEN1 subjects is prone to developing these types of cutaneous lesions and how they influence MEN1 evolution is still an open issue.

Multiple endocrine neoplasia type 2 (MEN2) and RET specific modifications of the ACMG/AMP variant classification guidelines and impact on the MEN2 RET database.

The Multiple Endocrine Neoplasia type 2 (MEN2) RET proto-oncogene database, originally published in 2008, is a comprehensive repository of all publicly available RET gene variations associated with MEN2 syndromes. The variant-specific genotype/phenotype information, age of earliest reported medullary thyroid carcinoma (MTC) onset, and relevant references with a brief summary of findings are cataloged. The ACMG/AMP 2015 consensus statement on variant classification was modified specifically for MEN2 syndromes and RET variants using ClinGen sequence variant interpretation working group recommendations and ClinGen expert panel manuscripts, as well as manuscripts from the American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma and other MEN2 RET literature. The classifications for the 166 single unique variants in the MEN2 RET database were reanalyzed using the MEN2 RET specifically modified ACMG/AMP classification guidelines (version 1). Applying these guidelines added two new variant classifications to the database (likely benign and likely pathogenic) and resulted in clinically significant classification changes (e.g., from pathogenic to uncertain) in 15.7% (26/166) of the original variants. Of those clinically significant changes, the highest percentage of changes, 46.2% (12/26), were changes from uncertain to benign or likely benign. The modified ACMG/AMP criteria with MEN2 RET specifications will optimize and standardize RET variant classifications.

Comparison Between Sporadic and Multiple Endocrine Neoplasia Type 1-Associated Insulinoma.

The differences between sporadic and multiple endocrine neoplasia type 1 (MEN-1)-associated insulinoma are not well described. Herein, we compared demographics, neoplasm characteristics, presentation, and survival in patients with sporadic vs MEN-1 insulinomas including benign and malignant disease. A retrospective study identified insulinoma patients. MEN-1 was defined based on genetic testing or clinically in patients with 2 or more primary MEN-1 tumor types. A total of 311 patients were identified: 84% benign and 16% malignant. The incidence of malignancy was similar (18% vs 16%, MEN-1 vs sporadic, p = 0.76). Within malignant patients, the median (interquartile range) age was 33 (25 ,44) years in MEN-1 vs 54 (41, 70) years in sporadic insulinoma (p = 0.04). There was no difference in sex or tumor size between MEN-1 and sporadic malignant insulinoma (p > 0.05). Of the 260 patients with benign insulinoma, 7% had MEN-1 syndrome. MEN-1 patients presented with insulinoma at a younger age: median (interquartile range) age was 38 (24, 49) years vs 52 (43, 65) years (p < 0.01). Resection of benign insulinoma was performed in 78% of the MEN-1 and 94% of the sporadic group (p = 0.03). Resected benign tumors were larger in the MEN-1 group: 2.0 (1.65, 2.45) cm vs 1.5 (1.2, 2.0) cm, respectively (p = 0.03). Concurrent insulinomas were more common in MEN-1 (17% vs 2%; p < 0.01). MEN-1 patients present with insulinoma at younger age and have larger benign pancreatic lesions at the time of resection compared with sporadic neoplasms. Younger patients and those with multifocal pancreatic neuroendocrine tumor in the setting of endogenous hyperinsulinism should be evaluated for MEN-1.

Pyoderma gangrenosum: examination and treatment experience

BACKGROUND: Pyoderma gangrenosum is a rare inflammatory skin disease that currently belongs to the group of neutrophilic dermatoses.
 AIMS: Development of epidemiological, clinical, laboratory characteristics of patients with pyoderma gangrenosum, as well as the treatment of this disease.
 MATERIALS AND METHODS: The study revealed 30 patients, 16 (53%) were women, the average age at the time of diagnosis was 5916.3 years. The most common localization of rashes was the lower leg 20 patients (67%), lesions of the skin of the face, genitals, and breast rarely noted, in one case, respectively. In 14 patients (47%), two or more ulcers were detected at the same time (max. 9 ulcers). The pathergy phenomenon was positive in 23 patients (77%) of 30. Ulcerative pyoderma gangrenosum occurred in 25 (83%), and extracutaneous pyoderma gangrenosum with lung involvement was identified in one patient. The most common associated disease was rheumatoid arthritis in 6 patients (20%), there were also rare associated diseases, such as hepatitis C two cases, multiple endocrine neoplasia syndrome type 1, autoimmune hepatitis, non-Hodgkins lymphoma by one observation. Histological examination revealed neutrophilic infiltration of the dermis in 30 patients (100%), and the presence of leukocytoclastic vasculitis in 16 (53%). Complete scarring during the treatment was observed in 22 patients (73%). Relapses during the observation period were observed in 12 patients (40%), the number of deaths was two cases.
 CONCLUSIONS: One of the largest case series of pyoderma gangrenosum to date is presented. During the examination of patients, it was found that neutrophilic infiltration of the dermis is a characteristic sign of the disease. Rare comorbidities (multiple endocrine neoplasia syndrome type 1, autoimmune hepatitis, hepatitis C, non-Hodgkins lymphoma) have been found. A sufficiently large percentage of relapses indicates the need for further research to develop an additional examination method for the purpose of modern diagnostics and justification for the timely prescription of targeted therapy.

[Clinical and laboratory features of hereditary pheochromocytoma and paraganglioma].

The widespread introduction of genetic testing in recent years has made it possible to determine that more than a third of cases of pheochromocytomas and paragangliomas (PPPGs) are caused by germline mutations. Despite the variety of catecholamine-producing tumors manifestations, there is a sufficient number of clinical and laboratory landmarks that suggest a hereditary genesis of the disease and even a specific syndrome. These include a family history, age of patient, presence of concomitant conditions, and symptoms of the disease. Considering that each of the mutations is associated with certain diseases that often determine tactics of treatment and examination of a patient, e.g. high risk of various malignancies. Awareness of the practitioner on the peculiarities of the course of family forms of PPPGs will allow improving the tactics of managing these patients.The article provides up-to-date information on the prevalence of hereditary PPPGs. The modern views on the pathogenesis of the disease induced by different mutations are presented. The main hereditary syndromes associated with PPPGs are described, including multiple endocrine neoplasia syndrome type 2A and 2B, type 1 neurofibromatosis, von Hippel-Lindau syndrome, hereditary paraganglioma syndrome, as well as clinical and laboratory features of the tumor in these conditions. The main positions on the necessity of genetic screening in patients with PPPGs are given.