Multiple Endocrine Neoplasia Type Research Articles

Beyond MEN1, When to Think About MEN4? Retrospective Study on 5600 Patients in the French Population and Literature Review.

Germline CDKN1B variants predispose patients to multiple endocrine neoplasia type 4 (MEN4), a rare MEN1-like syndrome, with <100 reported cases since its discovery in 2006. Although CDKN1B mutations are frequently suggested to explain cases of genetically negative MEN1, the prevalence and phenotype of MEN4 patients is poorly known, and genetic counseling is unclear. To evaluate the prevalence of MEN4 in MEN1-suspected patients and characterize the phenotype of MEN4 patients. Retrospective observational nationwide study. Narrative review of literature and variant class reassessment. We included all adult patients with class 3/4/5 CDKN1B variants identified by the laboratories from the French Oncogenetic Network on Neuroendocrine Tumors network between 2015 and 2022 through germline genetic testing for MEN1 suspicion. After class reassessment, we compared the phenotype of symptomatic patients with class 4/5 CDKN1B variants (ie, with genetically confirmed MEN4 diagnosis) in our series and in literature with 66 matched MEN1 patients from the UMD-MEN1 database. From 5600 MEN1-suspected patients analyzed, 4 with class 4/5 CDKN1B variant were found (0.07%). They presented with multiple duodenal NET, primary hyperparathyroidism (PHPT) and adrenal nodule, isolated PHPT, PHPT, and pancreatic neuroendocrine tumor. We listed 29 patients with CDKN1B class 4/5 variants from the literature. Compared with matched MEN1 patients, MEN4 patients presented lower NET incidence and older age at PHPT diagnosis. The prevalence of MEN4 is low. PHPT and pituitary adenoma represent the main associated lesions, NETs are rare. Our results suggest a milder and later phenotype than in MEN1. Our observations will help to improve genetic counseling and management of MEN4 families.

Does Genotype-Specific Phenotype in Patients with Multiple Endocrine Neoplasia Type 2 Occur as Current Guidelines Predict?

The clinical manifestation of multiple endocrine neoplasia type 2 (MEN2) in terms of developing medullary thyroid cancer (MTC), pheochromocytoma (PCC), and/or primary hyperparathyroidism (PHPT) is related to the respective pathogenic variant of the RET proto-oncogene. The aim of this study is to retrospectively analyze the individual, genotype-dependent clinical manifestations of a large cohort of MEN2 patients. By comparing their clinical profile with currently existing evidence-based knowledge, an optimal therapy and prevention strategy in terms of prophylactic thyroidectomy and clinical follow-up could be ensured. This is a retrospective single-center study of 158 MEN2 patients who were diagnosed and/or surgically treated at a tertiary referral care center between 1990 and 2022. All participants were categorized according to their pathogenic variant of the RET proto-oncogene. Subsequently, the clinical manifestation of the disease and its time of occurrence was documented. Our analysis showed results in line with existing studies, except for a considerably lower-than-predicted occurrence of PCC in patients with V804M/L mutations. This study supports the current recommendation regarding the pathogenic variant-dependent management of this rare cancer-associated syndrome.

Plasma miRNA expression in patients with genetically confirmed multiple endocrine neoplasia type 1 syndrome and its phenocopies

MEN-1 is a rare autosomal dominant disease caused by mutations in MEN1 gene encoding the menin protein. This syndrome is characterized by the occurrence of parathyroid tumors, gastroenteropancreatic neuroendocrine tumors, pituitary adenomas, as well as other endocrine and non-endocrine tumors. If a patient with the MEN-1 phenotype carry no mutations in the MEN1 gene, the condition considers a phenocopy of syndrome (phMEN1). The possible cause of this changes could be changes in epigenetic regulation, particularly in microRNA expression that might affect menin signaling pathways. to identify differently expressed circulating miRNAs in plasma in patients with genetically confirmed MEN-1 syndrome, its phenocopies and healthy controls. single-center, case-control study was conducted. We assessed plasma microRNA expression in patients with genetically confirmed MEN-1 (gMEN1), phMEN1 and healthy controls. Morning plasma samples were collected from fasting patients and stored at -80°C. Total RNA isolation was performed using miRNeasy Mini Kit with QIAcube. Thelibraries were prepared by the QIAseq miRNA Library Kit following the manufacturer. Circulating miRNA sequencing was done on Illumina NextSeq 500 (Illumina). Subsequent data processing was performed using the DESeq2 bioinformatics algorithm. we enrolled 21 consecutive patients with gMEN1 and 11 patients with phMEN1, along with 12 gender matched controls. Median age of gMEN1 was 38,0 [34,0; 41,0]; in phMEN1 - 59,0 [51,0; 60,0]; control - 59,5 [51,5; 62,5]. The gMEN1 group differed in age (p&lt;0.01) but not gender (р=0.739) or BMI (р=0.116) compared to phMEN1 and controls group, the last two groups did not differ by these parameters (p&gt;0.05). 25 microRNA were differently expressed in groups gMEN1 and phMEN1 (21 upregulated microRNAs, 4 - downregulated). Comparison of samples from the phMEN-1 group and relatively healthy controls revealed 10 differently expressed microRNAs: 5 - upregulated; 5 - downregulated. In the gMEN-1 and control groups, 26 differently expressed microRNAs were found: 24 - upregulated; 2 - downregulated. The miRNAs most differing in expression among the groups were selected for further validation by RT-qPCR (in the groups of gMEN1 vs phMEN1 - miR-3613-5p, miR-335-5p, miR-32-5p, miR-425-3p, miR-25-5p, miR-576-5p, miR-215-5p, miR-30a-3p, miR-141-3p, miR-760, miR-501-3p; gMEN1 vs control - miR-1976, miR-144-5p miR-532-3p, miR-375; as well as in phMEN1 vs control - miR-944, miR-191-5p, miR-98-5p). In a pilot study, we detected microRNAs that may be expressed differently between patients with gMEN-1 and phMEN-1. The results need to be validated using different measurement method with larger sample size.

Search for germinal mutations in insulin-producing pancreatic tumors

BACKGROUND: It is known that insulinoma in approximately 5% of cases is associated with multiple endocrine neoplasia type 1 syndrome (MEN1), in which the prognosis and management tactics of patients have been developed in detail. The diagnosis of MEN1 often does not require genetic confirmation, since the syndrome has a typical clinical picture. At the same time, a combination of this tumor with other hereditary syndromes is found in the literature, which are characterized by the presence of malignant neoplasms of various localizations, primary multiple lesions, hormonal and other disorders. Thus, it is relevant to search for the genetic causes that cause the development of insulinoma, in addition to MEN1.AIM: to evaluate the frequency of detection of genetic causes of the development of insulin-producing tumors of the pancreas, in addition to MEN1; to analyze the phenotypic characteristics of patients with such tumors.MATERIALS AND METHODS: Based on the analysis of literature for the period up to 2020, a panel has been developed that includes coding regions of 10 genes (MEN1, VHL, TSC1, TSC2, KRAS, YY1, CDKN2A, MLH1, ADCY1, CACNA2D2) involved in the development of insulinoma. In 32 patients diagnosed with insulinoma, verified by pathomorphological examination, with the absence of clinical and/or genetic data indicating MEN1 syndrome, a panel of genes was sequenced with subsequent analysis of the identified genetic variants and phenotypic data obtained from the medical records of patients. In one patient, an additional molecular genetic study of the «Endom» panel was performed, revealing genetic variants of coding regions of 377 genes associated with endocrine diseases.RESULTS: In 8 patients (25%, 95% CI (11%; 43%)), 9 variants of mutations were identified that were not classified as benign, at that two mutations in the TSC2 gene were detected in one patient. Frequencies of genetic variants: TSC2 — 13%, 95% CI (4%; 29%), MEN1 — 6% (1%; 21%), MLH1 — 3% (0%;16%), CDKN2A/P16INK4A — 3% (0%;16%). When comparing patients with the identified mutation, with the exception of benign (n=8), and patients without mutation or with a benign mutation (n=24), there were no differences in the Grade (degree of differentiation), Ki67 proliferation index, frequency of concomitant tumors, burdened history, multiple pancreatic lesions or recurrence of insulinoma, however, patients with germinal mutation were found at the level of statistical trend to be younger at the manifestation of insulinoma and to have bigger tumors. In a patient who underwent an additional molecular genetic study using the new «Endome» panel, previously undescribed gene variants (APC and KIF1B) associated with various sporadic tumors, including endocrine ones, were identified.CONCLUSION: A panel of 10 genes has been developed, mutations of which are associated with insulinoma. A relatively high incidence of genetically determined insulinoma was determined (25% of cases), in half of cases — against the background of tuberous sclerosis. We consider it relevant to evaluate the effectiveness of genetic testing for patients with insulinoma. We believe that, first of all, patients with a high risk of hereditary pathology should be examined: with the manifestation of the disease at a young age and with a large tumor. The identification of a genetic mutation will make it possible to determine the prognosis of the disease, optimize the monitoring algorithm in order to timely identify concomitant diseases-components of the hereditary syndrome, and conduct genetic counseling of the family.

Syndromic MEN1 parathyroid adenomas consist of both subclonal nodules and clonally independent tumors

Primary hyperparathyroidism with parathyroid tumors is a typical manifestation of Multiple Endocrine Neoplasia Type 1 (MEN1) and is historically termed “primary hyperplasia”. Whether these tumors represent a multi-glandular clonal disease or hyperplasia has not been robustly proven so far. Loss of Menin protein expression is associated with inactivation of both alleles and a good surrogate for a MEN1 gene mutation. The cyclin-dependent kinase inhibitor 1B (CDKN1B) gene is mutated in MEN4 and encodes for protein p27 whose expression is poorly studied in the syndromic MEN1 setting.Here, we analyzed histomorphology and protein expression of Menin and p27 in parathyroid adenomas of 25 patients of two independent, well-characterized MEN1 cohorts. The pattern of loss of heterozygosity (LOH) was assessed by fluorescence in situ hybridization (FISH) in one MEN1-associated parathyroid adenoma. Further, next-generation sequencing (NGS) was performed on eleven nodules of four MEN1 patients.Morphologically, the majority of MEN1 adenomas consisted of multiple distinct nodules, in which Menin expression was mostly lost and p27 protein expression reduced. FISH analysis revealed that most nodules exhibited MEN1 loss, with or without the loss of centromere 11. NGS demonstrated both subclonal evolution and the existence of clonally unrelated tumors.Syndromic MEN1 parathyroid adenomas therefore consist of multiple clones with subclones, which supports the current concept of the novel WHO classification of parathyroid tumors (2022). p27 expression was lost in a large fraction of MEN1 parathyroids and must therefore be used with caution in suggesting MEN4.

Precision medicine in endocrinology exemplified by medullary thyroid cancer

Medullary thyroid cancer (MTC) is a prime example for precision medicine in endocrinology and underlines the immediate benefits of basic, translational and healthcare research for patients with a rare disease in clinical . A mutation in the rearranged during transfection (RET) proto-oncogene that codes for a transmembrane receptor protein tyrosine kinase, leads to constitutive activation of the kinase, which is the decisive pathomechanism for the disease. The MTC occurs in a sporadic (somatic RET mutation) or hereditary form (RET germline mutation, multiple endocrine neoplasia types 2 and 3). For germline mutation carriers the timing of preventive thyroidectomy depends on the RET genotype. For advanced metastasized RET-mutant MTC, selective RET kinase inhibitors are available, which are currently considered to be game changers in the treatment. Based on the specific tumor marker calcitonin, MTC can be identified at an early stage during the differential diagnosis of thyroid nodules. The preoperative calcitonin level even enables statements on the degree of dissemination of the disease and on the probability of a cure through surgery. A new development is the consideration of desmoplasia as a histopathological biomarker for the metastatic potential of a MTC, which could possibly modify the operative approach as well as the future MTC nomenclature. Furthermore, the postoperative calcitonin level and the calcitonin doubling time are highly valid prognostic markers for tumor burden and biological aggressiveness of MTC and therefore decisive for patient follow-up. Biochemical, molecular and histological markers enable a risk-adapted surgical treatment and together with new targeted systemic treatments have contributed to a paradigm shift in the diagnostics, prognosis and treatment of MTC in recent years. Endocrine precision medicine for MTC therefore enabled a change from the previous purely symptom-oriented to a modern preventive and individualized treatment.

Whole-Exome Screening and Analysis of Signaling Pathways in Multiple Endocrine Neoplasia Type 1 Patients with Different Outcomes: Insights into Cellular Mechanisms and Possible Functional Implications.

Multiple endocrine neoplasia type 1 (MEN1) is a syndrome characterized by tumors in multiple organs. Although being a dominantly inherited monogenic disease, disease phenotypes are unpredictable and differ even among members of the same family. There is growing evidence for the role of modifier genes in the alteration of the course of this disease. However, genome-wide screening data are still lacking. In our study, we addressed the different outcomes of the disease, focusing on pituitary and adrenocortical tumors. By means of exome sequencing we identified the affected signaling pathways that segregated with those symptoms. Most significantly, we identified damaging alterations in numerous structural genes responsible for cell adhesion and migration. Additionally, in the case of pituitary tumors, genes related to neuronal function, survival, and morphogenesis were repeatedly identified, while in patients with adrenocortical tumors, TLR10, which is involved in the regulation of the innate immunity, was commonly modified. Our data show that using exome screening, it is possible to find signatures which correlate with the given clinical MEN1 outcomes, providing evidence that studies addressing modifier effects in MEN1 are reasonable.

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

P-47 Rare case of acromegaly due to plurihormonal pituitary adenoma and ACTH-independent Cushing syndrome

Abstract Introduction The concurrence of acromegaly and Cushing syndrome is infrequent. Pituitary adenomas are responsible for acromegaly and for Cushing syndrome in about 95% and 80% of cases respectively. Except adrenal adenoma, the other causes of Cushing syndrome remain rare. We here describe a case of a Tunisian patient with acromegaly due to plurihormonal pituitary adenoma and ACTH-independent Cushing syndrome with bilateral macronodules. Clinical Case A 35-year-old male patient was diagnosed with acromegaly by acrofacial dysmorphia. He had a family history of type 2 diabetes mellitus and hypertension but no endocrine diseases. He has diabetes mellitus for 15 years, hypertension and obstructive sleep apnea. Physical examination showed multiple blue nevi in the trunk. IGF-1 was elevated (1680ng/mL) and GH levels were not suppressed after an oral glucose load (nadir 78ng/mL). He had hypogonadotropic hypogonadism with normal prolactin (9,66ng/mL). Basal cortisol, FT4 and TSH levels were in the normal ranges. Pituitary MRI showed pituitary macroadenoma of 25×20.7 mm, invading both cavernous sinuses and compression of optic chiasma. He underwent transsphenoidal resection with histology confirming a prolactin, GH and LH co-secretory pituitary adenoma. He received postoperatively somatostatin analogue and cabergoline, in addition to external radiotherapy. Ultrasonography found infracentimetric EU-TIRADS 2 left nodule and multiple colloid cysts of the thyroid, testicles microlithiasis and no cardiac myxomas. Nine years after the diagnosis of acromegaly, bilateral adrenal adenomas (left:14 mm, right: 9 mm) were incidentally discovered by CT-scan done for abdominal pain. Low dose dexamethasone suppression test was carried out showing no suppression of cortisol and the low ACTH level confirmed ACTH-independent Cushing syndrome. Conclusion In our patient, at least two endocrine syndromes deserve to be mentioned. The first syndrome is Multiple Endocrine Neoplasia Type 1 but calcium and PTH levels were normal and there was no sign for neuroendocrine tumors. The second one is Carney's complex since our patient has acromegaly and multiple blue nevi which are two major criteria confirming the diagnosis. Cushing syndrome in Carney's complex is related to primary pigmented nodular adrenal disease characterized by micronodular hyperplasia. However, bilateral macronodules could be found in up to 30% of cases.

P-42 A delayed diagnosis of MEN1 syndrome

Abstract Introduction Multiple endocrine neoplasia 1 (MEN 1) is a rare autosomal dominantly inherited syndrome that results from mutations in the MEN1 gene. It is characterized by multiple tumors of endocrine glands and some other tissues. Early diagnosis is crucial for optimal management. Here we present a patient with delayed diagnosis and preventable metastatic disease. Clinical Case A 46-year-old male patient who was referred from gastroenterology clinic to our outpatient clinic following distal pancreatectomy. The postoperative pathology was reported as a well-differentiated neuroendocrine tumor (NET) with 3 focuses (60 mm, 9 mm and 2.5 mm in size). Six months ago, he underwent to Magnetic Resonance Imagination (MRI) of the abdomen because of abdominal pain and 17 kg weight loss in a year, that revealed a 69×67 mm cystic lesion in the tail of the pancreas (Figure 1A). Laboratory and physical examinations were in accordance with a nonfunctioning lesion (Table 1). The findings of the Gallium-68 DOTATATE PET/CT suggested residual and metastatic disease during follow-up (At the level of the pancreatic corpus, increased uptake was detected in two lesion sites adjacent to liver segment 3 and in various nodular lesion areas, the largest of which was approximately 20 mm in diameter, adjacent to the duodenum and pancreas (Figure 1B and 1D). No increased uptake was observed in the pancreas and these lesions in preoperative FDG/PET (Figure is not shown). The patient was consultated by oncology clinic and 177-Lutetium-DOTATATE and octreotide treatments were started. Parathyroidectomy and total thyroidectomy 7 years ago was noted in the patient's medical history. Persisting hypercalcemia and elevated PTH were also remarkable in laboratory testing (Table 2). The patient didn't apply to endocrinology clinic after parathyroidectomy and hypercalcemia had been overlooked for 7 years. Further investigation revealed a nonfunctioning 4 mm diameter pituitary lesion (Figure 1C). So the diagnosis of multiple endocrine neoplasia type 1 was suspected. Genetic test detected a c.784-2A&amp;gt;G spice site variant in MEN1 gene in heterozygous form. The patient denied a family history for MEN 1 but he reported that his father died at the age of 40 and his uncle at the age of 39 due to an illness of unknown origin, and two sons of the same uncle were followed up for parathyroid disease. Family screening and genetic counseling were recommended. Surgery of the remaining parathyroid glands and implantation in the forearm and thymectomy were planned. Conclusion MEN syndromes are rare and hypercalcemia is generally the initial presentation. Persistence of hypercalcemia following parathyroidectomy should be warning, and the possibility of MEN -1 syndrome should also be kept in mind even in the lack of family history. As in the presented case, diagnosis may be delayed due to late appearance of symptoms of other components, especially nonfunctional pancreaticoduodenal tumors.Figure 1.MRI and Ga-68 PET/CT images of the patientA: A 69×67 mm cystic lesion in the tail of the pancreas B: Increased Gallium-68 DOTATATE uptake at the level of the pancreatic corpus adjacent to liver segment 3 (SUVmax: 67.90) C: A nonfunctioning 4 mm diameter lesion in the right half of the pituitary D: Increased uptake of Gallium-68 DOTATATE in nodular lesions adjacent to the duodenum and pancreas (SUVmax: 31.09) Table 1.Laboratory results of the patientACTH: Adrenocorticotropic hormone, FSH: follicle stimulating hormone, LH: luteinizing hormone, IGF-1: Insülin-like growth factor, TSH: Thyroid stimulating hormone, 1 mg DST: dexamethasone suppression test Table 2.Calcium and PTH levels of the patient before parathyroidectomy and following parathyroidectomy*Before parathyroidectomy ** Following parathyroidectomy PTH: Parathyroid hormone

Familial multiple endocrine neoplasia type 1 with intrathoracic low-grade fibromyxoid sarcoma

BackgroundMultiple endocrine neoplasia type 1 (MEN1) is a hereditary tumor syndrome characterized by endocrine tumors with mainly a parathyroid, pancreatic, or anterior pituitary origin. Low-grade fibromyxoid sarcoma (LGFMS) is a rare low-grade soft tissue tumor. There is one known report of a patient with MEN1 complicated by LGFMS, which is very rare. Our report represents the second documented case, providing valuable insights.Case presentationA 31-year-old man with the chief complaint of a cough underwent chest contrast-enhanced computed tomography, which revealed a giant hypoabsorptive tumor with a maximum diameter of 23 cm in the left thoracic cavity. The patient was diagnosed with MEN1, as he also possessed a pancreatic neuroendocrine tumor and parathyroid tumor, and because his father had been found to have MEN1. To control hypercalcemia, surgery for the parathyroid tumor was initially performed, followed by surgical resection of the giant thoracic tumor for diagnosis and treatment. Histopathological examination findings of the tumor resulted in a diagnosis of LGFMS.ConclusionWe experienced a very rare MEN1 with LGFMS. Although endocrine tumors generally occur more frequently in MEN1, non-endocrine tumors such as the present case should also be noted, reinforcing the importance of systemic imaging scrutiny in addition to early diagnosis and long-term follow-up of MEN1 patients.

Individualized approach for MEN1-associated duodenopancreatic neuroendocrine neoplasms

Multiple endocrine neoplasia type 1 (MEN1)-associated duodenopancreatic neuroendocrine neoplasms (dpNEN) represent the most frequent syndrome-associated cause of death, but the adequate treatment is sometimes considered controversial. Presentation of possible diagnostic and therapeutic options for MEN1-associated dpNENs. In this review article retrospective case studies, expert recommendations, national and international guidelines as well as personal experiences were analyzed and evaluated. Due to early detection programs and the use of the most modern imaging techniques, dpNEN are nowadays diagnosed much earlier. Nonfunctional pNENs currently represent the most frequent dpNENs with about 70%, followed by gastrinomas and insulinomas. Regardless of their functional activity, dpNENs with asize of > 2 cm are generally an indication for surgery. The choice of the optimal treatment strategy, however, in most cases remains the subject of controversial discussions, although nowadays surgery should always be performed in an organ-preserving and minimally invasive way when feasible. Recurrences or new dpNENs are expected in more than 60% of cases, necessitating areoperation in up to 40% of these cases. Duodenopancreatic resections and reoperations can be carried out safely by experienced practitioners and with an acceptable level of risk. The planning of treatment requires careful consideration of the suitable timing, the extent of the operation, the risk of recurrence and potential morbidities. Furthermore, preserving pancreatic function and the quality of life is of utmost importance. In view of the complexity of the disease, MEN1 patients should be treated in specialized centers.

Pancreatic GHRHomas in Patients with or without Multiple Endocrine Neoplasia Type 1 (MEN 1) : An Analysis of 36 Reported Cases.

Pancreatic GHRHomas (pGHRHomas) with acromegaly have unique conditions, harboring the existence of multiple endocrine neoplasia type 1 (MEN 1). Moreover, pituitary lesions are affected by both protracted ectopic GHRH and loss of menin function. Of significance is the clarification of clinicopathological aspects of pGHRHomas in patients with or without MEN 1. From 1977-2016, thirty-six patients with pGHRHomas were reported. Twenty-two out of 36 patients (61%) had pGHRHomas with MEN 1 and 14 patients did not. The former had a tendency of male predominance, benign tumor behavior and fewer metastasis rather than the latter. The latter is a single pGHRHoma accompanied by pituitary enlargement with somatotroph hyperplasia (hyperplasia) caused by protracted ectopic GHRH. Nine patients with MEN 1 underwent transsphenoidal surgery (TSS). The hyperplasia associated with various pituitary adenomas (PAs) including three GH-related adenomas was observed in seven subjects (32%). In these patients, the resection of their pGHRHomas was feasible. Furthermore, all patients with acromegaly due to pGHRHomas without MEN 1 had non-TSS, whereas approximately 70% of those with MEN 1 had unnecessary TSS. The association with hyperplasia and various PAs suggested that formation of the three GH-related adenomas may be induced by the foundations of MEN 1 gene mutations. J. Med. Invest. 71 : 1-8, February, 2024.

Pancreatic Neuroendocrine Tumor in a Patient With Multiple Endocrine Neoplasia Type 4

Pancreatic Neuroendocrine Tumor in a Patient With Multiple Endocrine Neoplasia Type 4

Primary Hyperparathyroidism in Young and Adolescents: Alike or Unlike Adult Hyperparathyroidism? - A Series from South India.

Primary hyperparathyroidism (PHPT) is a common endocrine condition but rare in the pediatric and adolescent populations. The presentations can be unique, accounting for significant morbidity in the case of untimely detection. To study surgically treated pediatric PHPT retrospectively. Surgically treated children of PHPT up to 20 years of age between 2010 to 2022 were analyzed. All of them were operated on by an endocrine surgeon and team. There was a total of 712 parathyroidectomies over 12 years, out of which there were 52 children (7.3%) had PHPT at less than 20 years of age. This group included 32 male children. The mean age was 16.1 years, including 7 cases of neonatal severe HPT. Multiple Endocrine Neoplasia type 1 was confirmed in 12 children. Presentations were more severe like bone pain (35.13%), renal stones (27.02%), incidental asymptomatic detection (18.9%), failure to thrive (10.8%), and pancreatitis (8.1%) as compared to adults. Mean serum calcium was 12.9 mg/dl (highest-14.1, N-8.8-10.8 mg/dl), mean parathormone levels were 386.91 pg/ml (N-10-65) and vitamin D levels ranged from 2.9-22.8 ng/ml. Localization was done with ultrasound and 99mTc- SESTAMIBI scans. Mean serum calcium levels in NSPHPT were 28.6 mg/dl (N-8.8-10.8 mg/dl). There were a total of 45 cases (6.32%) of PHPT less than 20 years of age, excluding the cases of NSPHPT. All children underwent parathyroidectomy, with 14 cases having an additional thymectomy, 2 cases with thyroidectomy, and a single case of hemithyroidectomy. The cure rate was 97.3%, while one baby with NSPHPT had persistent disease (postop PTH-110 pg/ml). The uniglandular disease was seen in 54.05% and the rest had a multiglandular disease. Adults accounted for 559/660 cases with 80% uniglandular disease. All cases had a postoperative histopathological confirmation with an average follow-up of 1 year. Childhood PHPT has a few features same as the adult population. Symptomatic presentations like adults, though pancreatitis and fatigue were more commonly seen as compared to bone pain. Calcium, phosphorus, and parathormone levels were comparable. Uniglandular involvement was seen just like the adult population. There are a few others that make them a distinct subtype like their symptoms of bone pain and being more common among boys. One-fourth of them had MEN1. Fewer cases in this age group make them unique.

The risk of concurrent malignancies in patients with multiple endocrine neoplasia type 1: insights into clinical characteristics of those with multiple endocrine neoplasia type 1.

Summarize and analyze the characteristics of patients with Multiple Endocrine Neoplasia type 1 (MEN-1) who were diagnosed with malignant tumors that do not belong to MEN-1 components. Clinical data from patients with MEN-1 who visited Peking Union Medical College Hospital between April 2012 and April 2022 were collected. We compared the clinical characteristics of patients with malignant tumors outside of their MEN-1 components to those without additional tumors. MEN-1 gene testing was performed on most of these patients using Sanger sequencing, whole-exome sequencing, or MLPA. A total of 221 MEN-1 patients were diagnosed, of which 23 (10.40%) were found to have malignant tumors that did not belong to MEN-1 components, including papillary thyroid carcinoma (PTC) (4.52%), breast cancer (1.81%), urologic neoplasms (1.35%), primary hepatic carcinoma (PCC) (0.09%), meningeal sarcoma (0.05%), glioblastoma (0.05%), cervical cancer (0.05%), and lung carcinoma (0.05%). MEN-1 gene mutations were identified in 11 patients, including missense mutations, frameshift mutations, and splice mutations. The prevalence of each endocrine neoplasm, particularly gastroenteropancreatic neuroendocrine tumor, was higher in MEN-1 patients with other malignant tumors compared to MEN-1 patients without malignant tumors. Our retrospective study revealed a higher incidence of non-MEN-1 component malignant tumors in MEN-1 patients, especially breast cancer, PTC, and urologic neoplasms. These patients also exhibit more severe clinical phenotypes of MEN-1.

Impact of Early Diagnostic and Therapeutic Interventions and Clinical Course in Children and Adolescents with Multiple Endocrine Neoplasia Types 1 and 2.

Multiple endocrine neoplasia types 1 (MEN1) and 2 (MEN2) are inherited endocrine tumor syndromes caused by mutations in the MEN1 or RET genes. This study aimed to investigate clinical outcomes and molecular characteristics among children with MEN. This study included eight patients from seven unrelated families. Data on clinical course, biochemical findings, and radiologic studies were collected by retrospective chart review. All diagnoses were genetically confirmed by Sanger sequencing of MEN1 in three MEN1 patients and RET in four patients with MEN2A and one patient with MEN2B. Three patients with MEN1 from two families presented with hypoglycemia at a mean age of 11±2.6 years. Four patients with MEN2A were genetically diagnosed at a mean of 3.0±2.2 years of age by family screening; one of them was prenatally diagnosed by chorionic villus sampling. Three patients with MEN2A underwent prophylactic thyroidectomy from 5 to 6 years of age, whereas one patient refused surgery. The patient with MEN2B presented with a tongue neuroma and medullary thyroid carcinoma at 6 years of age. Subsequently, he underwent a subtotal colectomy because of bowel perforation and submucosal ganglioneuromatosis at 18 years of age. This study described the relatively long clinical course of pediatric MEN with a mean follow-up duration of 7.5±3.8 years. Insulinoma was the first manifestation in children with MEN1. Early diagnosis by family screening during the asymptomatic period enabled early intervention. The patient with MEN2B exhibited the most aggressive clinical course.

A clinical case of multiple endocrine neoplasia type 1 syndrome

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Bilateral pheochromocytoma in patients with von Hippel–Lindau syndrome: clinical and molecular genetic features

Bilateral adrenal pheochromocytoma (PCС) is extremely rare in children, with major predisposing factors being multiple endocrine neoplasia type 2 and von Hippel–Lindau syndrome. In case of bilateral PCC with underlying von Hippel–Lindau syndrome, organ-preserving surgery is preferred in view of the low malignant potential of such neoplasms. We aimed to study clinical and molecular genetic features of patients with bilateral adrenal PCCs treated at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of the Russian Federation. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of the Russian Federation. The study included 20 patients with paraganglioma (PGL)/PCC (PPGL) who had received treatment (n = 17) or outpatient care (n = 3) at the Center over the period from 2012 to 2023. Bilateral adrenal PCC was diagnosed in 4 (20%) patients. In all these cases, the diagnosis was confirmed by histology. Molecular genetic testing was carried out at the Laboratory of Molecular Biology at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of the Russian Federation in order to search for germline pathogenic variants in PCC/PGL susceptibility genes. The median age of the four patients with bilateral adrenal PCC was 9.5 years (range 4.5–14.6 years). All the patients were male. In one patient, synchronous bilateral PCC/PGL was observed. In 100% of the cases, arterial hypertension was diagnosed at the onset of the primary disease and was treated with alpha-blockers as part of preparation for surgery. According to the results of a 24-hour urine biochemistry test, all the patients had at least a 4-fold increase above the upper limit of normal for normetanephrine levels. Molecular genetic testing using the multiplex ligation-dependent probe amplification method revealed a pathogenic germline variant in exon 3 of the VHL gene in all the children (4/4). Hereditary PPGL was proven in 2/4 (50%) patients. In all the cases, R0/R1 resection was achieved. Organ-sparing surgery on one/two adrenal glands was performed in 3/4 cases. One out of four (25%) patients developed a local relapse 18.4 months after diagnosis. The overall survival rate in this group was 100%, with a median follow-up time of 8.1 months (range 0.8–50.2 months). Bilateral adrenal PCC is a very rare childhood tumor. A medical genetic consultation is necessary to identify tumor predisposition syndromes. A multidisciplinary team discussion of a surgical strategy is recommended, with organ-sparing surgery on one or two adrenal glands being the treatment of choice that should be carried out at centers specializing in pediatric surgical oncology. Here, we report a rare clinical case of bilateral retroperitoneal PCC/PGL in a patient with von Hippel-Lindau syndrome. The patient's parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.

Beyond the three P's: adrenal involvement in MEN1.

Adrenal lesions (ALs) are often detected in patients with multiple endocrine neoplasia type 1 (MEN1). However, they are not well described in MEN1, making their clinical management unclear. This study examined the prevalence and outcomes of ALs found in MEN1. We performed a retrospective chart review of patients diagnosed with MEN1 from 1990 to 2021. ALs were diagnosed using abdominal or thoracic imaging and classified as being unilateral or bilateral, having single or multiple nodules, and as having diffuse enlargement or not. Measurable nodular lesions were analyzed for their size and growth over time. Patients' clinical and radiographic characteristics were collected. We identified 382 patients with MEN1, 89 (23.3%) of whom had ALs. The mean age at detection was 47 ± 11.9 years. We documented 101 measurable nodular lesions (mean size, 17.5 mm; range, 3-123 mm). Twenty-seven nodules (26.7%) were smaller than 1 cm. Watchful waiting was indicated in 79 (78.2%) patients, of whom 28 (35.4%) had growing lesions. Functional lesions were diagnosed in 6 (15.8%) of 38 that had functional work-up (diagnoses: pheochromocytoma (n = 2), adrenocorticotropic hormone-dependent hypercortisolism (n = 2), hyperandrogenism (n = 1), hyperaldosteronism (n = 1)); surgery was indicated for 5 (83.3%; n = 12 nodules), 2 of whom had bilateral, diffuse adrenal enlargement. Two patients were diagnosed with adrenocortical carcinoma and two with neoplasms of uncertain malignant potential. Radiographic or clinical progression of ALs is uncommon. Malignancy should be suspected on the basis of a lesion's growth rate and size. A baseline hormonal work-up is recommended, and no further biochemical work-up is suggested when the initial assessment shows nonfunctioning lesions.