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A personalized approach to the management of medullary thyroid cancer (MTC) presents several challenges; however, in the past decade significant progress has been made in both diagnostic and treatment modalities. Germline rearranged in transfection (RET) testing in multiple endocrine neoplasia 2 and 3, and somatic RET testing in sporadic MTC have revolutionized the treatment options available to patients. Positron emission tomography imaging with novel radioligands has improved characterization of disease and a new international grading system can predict prognosis. Systemic therapy for persistent and metastatic disease has evolved significantly with targeted kinase therapy especially for those harboring germline or somatic RET variants. Selpercatinib and pralsetinib are highly selective RET kinase inhibitors that have shown improved progression-free survival with better tolerability than outcomes seen in earlier multikinase inhibitor studies. Here we discuss changes in paradigms for MTC patients: from determining RET alteration status upfront to novel techniques for the evaluation of this heterogenous disease. Successes and challenges with kinase inhibitor use will illustrate how managing this rare malignancy continues to evolve. [ABSTRACT FROM AUTHOR]

Abstract Thymic neuroendocrine tumors associated with multiple endocrine neoplasia are only defined as carcinoid and are not associated with large‐cell neuroendocrine carcinoma (LCNEC). We report the case of a multiple endocrine neoplasia type 1 patient with atypical carcinoid tumors with elevated mitotic counts (AC‐h), an intermediate condition between carcinoid and LCNEC. A 27‐year‐old man underwent surgery for an anterior mediastinal mass and was diagnosed with thymic LCNEC. Fifteen years later, a mass appeared at the same site, which was determined to be a postoperative recurrence based on the pathological results of a needle biopsy and the clinical course. The patient's disease remained stable for 10 months on anti‐programmed death‐ligand 1 antibody and platinum‐containing chemotherapy. The needle biopsy specimen was submitted for next‐generation sequencing, which revealed a MEN1 gene mutation, and after further examination, a diagnosis of multiple endocrine neoplasia type 1 was made. A re‐examination of the surgical specimen from 15 years prior showed that it corresponded to AC‐h. Although thymic AC‐h is classified as thymic LCNEC according to the current definition, our data suggests that a search for multiple endocrine neoplasia is warranted in such patients.

Multiple endocrine neoplasia type 2 (MEN Type 2) syndrome (Sipple syndrome) is a syndrome associated with mutations in the autosomal dominant inherited RET protooncogene. MEN Type 2 syndrome, which has three clinical subtypes, the clinical findings of the MEN 2A subtype are medullary thyroid carcinoma, primary hyperparathyroidism, and pheochromocytoma. In the literature, patients diagnosed with MEN 2A are often first presented with medullary thyroid carcinoma. Cases of MEN 2A presenting with parathyroid adenoma firstly are rare. In this case, an 18-year-old female patient who came to the internal medicine outpatient clinic with complaints of flank pain lasting for four years, nausea and headache for a month, was hospitalized to the internal medicine endocrinology clinic for further examinations. The patient was consulted to the otorhinolaryngology clinic because the patient's parathormone and blood calcium levels were high in the examinations and parathyroid adenoma was observed in the scintigraphy. Frozen tissue sample of operated patient’s was compatible with parathyroid adenoma. The patient, whose blood calcium and parathormone levels were high after the operation, was rehospitalized to the endocrinology clinic. Pheochromocytoma diet was applied to the patient whose genetic test result was reported as multiple endocrine neoplasia type 2A. Thyroid nodule was observed in the neck ultrasonography. As a result of this, fine needle aspiration biopsy was performed on the patient. After total thyroidectomy was performed to the patient whose fine needle aspiration biopsy was reported as medullary thyroid carcinoma, the patient's clinical and laboratory findings regressed.

Medullary thyroid carcinoma (MTC) is the third most prevalent thyroid cancer and the most invasive form. This malignancy could be presented either in a sporadically or a familial pattern. Although the majority of cases with this disease are presented sporadically, familial screening is of great necessity in every MTC case since of all heritable cancers, MTCs are the most common malignancies. Therefore, after the familial screening of MTC patients using clinical symptoms along with paraclinical tools, the present study identified 19 familial medullary thyroid carcinoma (FMTC) cases in one family. Since most FMTCs are associated with multiple endocrine neoplasia’s (MEN's) syndrome, it has attracted a great deal of scientific attention. This syndrome was ruled out herein through both genetic and clinical testing in these individuals. Thus, due to the scarcity of the familial form of this disease, the significant number of MTC in a family, and the absence of MEN syndrome in these people, we decided to report 19 patients with MTC in the same family without MEN’s syndrome from southwest of Iran; this report emphasizes the necessity of familial screening even in the absence of the MEN's syndrome.

The article discusses a case study of a 64-year-old male patient with a slow-growing thyroid mass. Topics include the clinical presentation of the patient, with a neck swelling; the role of diagnostic imaging, such as ultrasound and CT scans; and the diagnosis and treatment of medullary thyroid carcinoma (MTC), with Fine Needle Aspiration Cytology confirming MTC, leading to a successful thyroidectomy and right functional neck dissection.

Thyroid surgery in children results from three main etiologies: Medullary thyroid cancer in MEN syndromes, benign disease most often Graves' disease, and thyroid nodules which may harbor differentiated thyroid cancers. I will discuss the evaluation of these etiologies, pre-operative preparation, and operative strategies for each of these pediatric thyroid problems. [ABSTRACT FROM AUTHOR]

Simple Summary: The surface of a human cell is coated by glycans, which play an important role in many of the physiological processes that include cell–cell communication, interaction, and adhesion. The aberration of the process of glycan synthesis plays a role in inflammatory conditions, tumour progression and metastasis. The process of O-glycosylation is complex and takes place in the Golgi apparatus, regulated by specific enzymes called ppGalNAc transferases. The incomplete synthesis or truncated forms of O-glycans such as Tn, STn, T and ST antigens are commonly seen in cancer states. The increased expression of these truncated glycans is associated with increased invasion potential, leading to metastasis and poor prognosis in a wide range of cancers. Understanding the expression of truncated glycans by cancers paves the way for targeted therapies, which have the potential to be used as serum biomarkers of disease progression and prognosis. Glycans are an essential part of cells, playing a fundamental role in many pathophysiological processes such as cell differentiation, adhesion, motility, signal transduction, host–pathogen interactions, tumour cell invasion, and metastasis development. These glycans are also able to exert control over the changes in tumour immunogenicity, interfering with tumour-editing events and leading to immune-resistant cancer cells. The incomplete synthesis of O-glycans or the formation of truncated glycans such as the Tn-antigen (Thomsen nouveau; GalNAcα- Ser/Thr), its sialylated version the STn-antigen (sialyl-Tn; Neu5Acα2–6GalNAcα-Ser/Thr) and the elongated T-antigen (Thomsen–Friedenreich; Galβ1-3GalNAcα-Ser/Thr) has been shown to be associated with tumour progression and metastatic state in many human cancers. Prognosis in various human cancers is significantly poor when they dedifferentiate or metastasise. Recent studies in glycobiology have shown truncated O-glycans to be a hallmark of cancer cells, and when expressed, increase the oncogenicity by promoting dedifferentiation, risk of metastasis by impaired adhesion (mediated by selectins and integrins), and resistance to immunological killing by NK cells. Insight into these truncated glycans provides a complimentary and attractive route for cancer antigen discovery. The recent emergence of immunotherapies against cancers is predicted to harness the potential of using such agents against cancer-associated truncated glycans. In this review, we explore the role of truncated O-glycans in cancer progression and metastasis along with some recent studies on the role of O-glycans in endocrine cancers affecting the thyroid and adrenal gland. [ABSTRACT FROM AUTHOR]

Between 2% and 10% of patients with primary hyperparathyroidism (pHPT) are diagnosed with hereditary forms of primary hyperparathyroidism (hpHPT). They are more prevalent in younger patients before the age of 40 years, in patients with persistence or recurrence of pHPT and pHPT patients with multi-glandular disease (MGD). The various forms of hpHPT diseases can be classified into four syndromes, i.e., hpHPT associated with diseases of other organ systems, and four diseases that are confined to the parathyroid glands. Approximately 40% of patients with hpHPT suffer from multiple endocrine neoplasia type 1 (MEN-1) or show germline mutations of the MEN‑1 gene. Currently, germline mutations that lead to a specific diagnosis in patients with hpHPT have currently been described in 13 different genes, which enables a clear diagnosis of the disease; however, a clear genotype-phenotype correlation does not exist, even though the complete loss of a coded protein (e.g. due to frame-shift mutations in the calcium sensing receptor, CASR) often leads to more severe clinical consequences than merely a reduced function of the protein (e.g. due to point mutation). As the various hpHPT diseases require different treatment approaches, which do not correspond to that of sporadic pHPT, a clear definition of the specific form of hpHPT must always be strived for. Therefore, before surgery of a pHPT with clinical, imaging or biochemical suspicion of hpHPT, genetic proof or exclusion of hpHPT is necessary. The differentiated treatment approach for hpHTP can only be defined by taking the clinical and diagnostic results of all the abovenamed findings into account. [ABSTRACT FROM AUTHOR]

An ~10-y-old male sheep had anorexia and progressive weight loss for ~1 mo. The sheep was emaciated, and 20 d later, became recumbent and lethargic, and was hypoglycemic (0.33 mmol/L; RI: 2.6–4.4 mmol/L). The sheep was euthanized because of poor prognosis, and submitted for autopsy. We found no gross lesions in the pancreas; however, histologically, focal proliferations of round-to-polygonal cells were separated by connective tissue into small nests. These proliferating cells, which had abundant eosinophilic-to-amphophilic cytoplasm and hyperchromatic nuclei, were immunopositive for insulin and negative for glucagon and somatostatin; the lesion was diagnosed as an insulinoma. Insulinoma has not been reported previously in sheep, to our knowledge. In addition, autopsy and histologic examination revealed the presence of an adrenocortical carcinoma with myxoid differentiation and a thyroid C-cell carcinoma. Our case indicates that multiple endocrine neoplasms can occur in sheep, as in other animal species. [ABSTRACT FROM AUTHOR]

Background: Multiple endocrine neoplasia (MEN) occurs throughout the body with an array of symptoms. Its management is challenging. Diet-mediated immune dysfunction may provoke their pathogenesis and clinical symptoms. Hence, diet-mediated immune optimization strategies may be useful for their management and prevention. Objective: The objective of this study was to discuss our putative diet-mediated immune dysfunction model of cancers using MEN as a classic disease paradigm. Materials and Methods: Online searches on databases such as Google Scholar, PubMed, Biomed Central, Directorate of Open Access Journal (DOAJ), and SciELO were carried out. An attempt was made to review articles with keywords such as cancer, tumor immunology, MEN, diet and immune system, T lymphocyte activation/dysfunction, and cytokines in cancers. Results: Putative diet-mediated immune dysfunction mechanisms in MEN and diet-mediated immune optimization strategies were found to be useful in preventing MEN, and as effective therapeutic adjuncts for management of MEN. Conclusion: Diet-mediated immune optimization could serve as a preventive and therapeutic adjunct for the management of MEN and other cancers.

Childhood adrenocortical carcinoma (ACC) is a rare disease that is mostly linked to familial cancer syndrome. Although the prevalence of ACC is extremely low in children, it is clinically important to diagnose ACC early because age and tumor stage are closely related to prognosis. From this perspective, understanding the underlying genetics and possible symptoms of ACC is crucial in managing ACC with familial cancer syndromes. In this report, we present the case of a 3-year-old girl who initially presented with symptoms of precocious puberty and was later found to have ACC by imaging analysis. On genetic analysis, the patient was found to have a MEN1 gene mutation. MEN1 mutations are found in patients with multiple endocrine neoplasia type 1 (MEN1), usually precipitating multiple endocrine tumors, including pituitary adenoma, parathyroid hyperplasia, and adrenal tumors. Although MEN1 mutation is usually inherited in an autosomal dominant manner, neither of the patient’s parents had the same mutation, making hers a case of sporadic MEN1 mutation with initial presentation of ACC. The clinical course and further investigations of this patient are discussed in detail in this report.

Thymic neuroendocrine tumors associated with multiple endocrine neoplasia are only defined as carcinoid and are not associated with large‐cell neuroendocrine carcinoma (LCNEC). We report the case of a multiple endocrine neoplasia type 1 patient with atypical carcinoid tumors with elevated mitotic counts (AC‐h), an intermediate condition between carcinoid and LCNEC. A 27‐year‐old man underwent surgery for an anterior mediastinal mass and was diagnosed with thymic LCNEC. Fifteen years later, a mass appeared at the same site, which was determined to be a postoperative recurrence based on the pathological results of a needle biopsy and the clinical course. The patient's disease remained stable for 10 months on anti‐programmed death‐ligand 1 antibody and platinum‐containing chemotherapy. The needle biopsy specimen was submitted for next‐generation sequencing, which revealed a MEN1 gene mutation, and after further examination, a diagnosis of multiple endocrine neoplasia type 1 was made. A re‐examination of the surgical specimen from 15 years prior showed that it corresponded to AC‐h. Although thymic AC‐h is classified as thymic LCNEC according to the current definition, our data suggests that a search for multiple endocrine neoplasia is warranted in such patients. [ABSTRACT FROM AUTHOR]

Objective: This study aims to evaluate the presence of multiple endocrine neoplasia-1 mutations in patients with primary hyperparathyroidism detected on clinical and sonographical suspicion. Methods: We scanned the medical records of 361 patients with primary hyperparathyroidism between January 2010 and December 2017. Results: Fourteen of 361 patients (i.e., 2 males and 12 females) with primary hyperparathyroidism were evaluated genetically upon clinical and sonographical suspicion. Menin gene mutations were found in 3 of 14 patients (21.4%) patients. The frequency of multiple endocrine neoplasia-1 (n = 3) was estimated to be 0.83% in all patients with primary hyperparathyroidism (n = 361). Data of 4 patients with menin mutation analyses were as follows: case 1: A 37-year-old man presented with a 14-year history of recurring nephrolithiasis. He was diagnosed with primary hyperparathyroidism. Genetic analysis was reported as multiple endocrine neoplasia-1: c.643_646delACAG (p. Thr215Serfs*13) heterozygote; case 2: A 35-year-old man with primary hyperparathyroidism and prolactinoma was diagnosed. Genetic analysis was reported as multiple endocrine neoplasia-1: c.654+1G>A heterozygote; case 3: A 26-year-old woman with hyperammonemia, partial empty sella, and hyperprolactinemia was evaluated. Genetic testing revealed heterozygote genomic changes in c984c>a in the multiple endocrine neoplasia-1 gene on the seventh exon; case 4: A 27-year-old man was diagnosed with nephrolithiasis when he was 19 years old. He had both primary hyperparathyroidism and prolactinoma. Multiple endocrine neoplasia-1 and CDKN1B genetic mutation analyses were negative. Because mutation-negative syndromes could not be ruled out, a neck exploration was performed, and a parathyroid adenoma was excised. Conclusions: Patients with primary hyperparathyroidism should be evaluated for multiple endocrine neoplasia-1 mutations upon clinical and sonographical suspicion. It should be noted that an individual with the multiple endocrine neoplasia-1 gene mutation has a 100% penetrance up to the age of 40-50 years. Additionally, 2 novel multiple endocrine neoplasia-1 mutations were identified. [ABSTRACT FROM AUTHOR]

Medullary thyroid carcinoma (MTC) is the third most prevalent thyroid cancer and the most invasive form. This malignancy could be presented either in a sporadically or a familial pattern. Although the majority of cases with this disease are presented sporadically, familial screening is of great necessity in every MTC case since of all heritable cancers, MTCs are the most common malignancies. Therefore, after the familial screening of MTC patients using clinical symptoms along with paraclinical tools, the present study identified 19 familial medullary thyroid carcinoma (FMTC) cases in one family. Since most FMTCs are associated with multiple endocrine neoplasia's (MEN's) syndrome, it has attracted a great deal of scientific attention. This syndrome was ruled out herein through both genetic and clinical testing in these individuals. Thus, due to the scarcity of the familial form of this disease, the significant number of MTC in a family, and the absence of MEN syndrome in these people, we decided to report 19 patients with MTC in the same family without MEN's syndrome from southwest of Iran; this report emphasizes the necessity of familial screening even in the absence of the MEN's syndrome. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we employed a cell-based assay with a luciferase gene controlled by the RET promoter to identify small molecules that inhibit the transcription of the RET gene. The RET gene plays a role in the development of medullary thyroid carcinoma (MTC) as part of multiple endocrine neoplasia type 2 (MEN2) syndrome. Adefovir dipivoxil was found to inhibit the transcription of the RET gene, reducing the expression of endogenous RET protein, inhibiting RET-dependent cell proliferation, and increasing apoptosis in MTC cells. Additionally, adefovir dipivoxil was found to interfere with Stat3 activity both in silico and in a biochemical assay, as well as in MTC cell lines. These results suggest that the cell-based assay is useful in identifying transcriptional inhibitors for oncogenes and has potential as a strategy to control cancer growth and development. Aberrant gene expression is often linked to the progression of various cancers, making the targeting of oncogene transcriptional activation a potential strategy to control tumor growth and development. The RET proto-oncogene's gain-of-function mutation is a major cause of medullary thyroid carcinoma (MTC), which is part of multiple endocrine neoplasia type 2 (MEN2) syndrome. In this study, we used a cell-based bioluminescence reporter system driven by the RET promoter to screen for small molecules that potentially suppress the RET gene transcription. We identified adefovir dipivoxil as a transcriptional inhibitor of the RET gene, which suppressed endogenous RET protein expression in MTC TT cells. Adefovir dipivoxil also interfered with STAT3 phosphorylation and showed high affinity to bind to STAT3. Additionally, it inhibited RET-dependent TT cell proliferation and increased apoptosis. These results demonstrate the potential of cell-based screening assays in identifying transcriptional inhibitors for other oncogenes. [ABSTRACT FROM AUTHOR]

Simple Summary: The vault complex, consisting of a major vault protein (MVP), two minor vault proteins (VPARP and TEP1), and small untranslated vault RNA molecules, is considered the largest intracellular ribonucleoprotein particle. Although in recent years vaults were believed to be involved in multidrug resistance (MDR), the exact function of this complex has remained unclear. Our findings reveal a so far unexplored role of the vault complex that is closely linked to the therapeutic responsiveness of endocrine tumors. Cancers display dynamic interactions with their complex microenvironments that influence tumor growth, invasiveness, and immune evasion, thereby also influencing potential resistance to therapeutic treatments. The tumor microenvironment (TME) includes cells of the immune system, the extracellular matrix, blood vessels, and other cell types, such as fibroblasts or adipocytes. Various cell types forming this TME secrete exosomes, and molecules thereby released into the TME have been shown to be important mediators of cellular communication and interplay. Specific stressors in the TME, such as hypoxia, starvation, inflammation, and damage, can furthermore induce autophagy, a fundamental cellular process that degrades and recycles molecules and subcellular components, and recently it has been demonstrated that the small non-coding vault RNA1-1 plays a role as a regulator of autophagy and the coordinated lysosomal expression and regulation (CLEAR) network. Here, we demonstrate for the first time that intra-tumoral damage following effective therapeutic treatment is linked to specific intracellular synthesis and subsequent exosomal release of vault RNAs in endocrine tumors in vitro and in vivo. While we observed a subsequent upregulation of autophagic markers under classical chemotherapeutic conditions, a downregulation of autophagy could be detected under conditions strongly involving inflammatory cascades. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant disorder without a good genotype–phenotype correlation, characterized by tumor predisposition in the parathyroid gland, anterior pituitary, and pancreatic islet cells. Here, we describe a 37‐year‐old male with previous history of nephrolithiasis, with a 1‐year history of recurrent hypoglycemic episodes. Physical examination revealed the presence of two lipomas. Family history revealed primary hyperparathyroidism (PHPT), hyperprolactinemia, and multiple non‐functioning pancreatic neuroendocrine tumors. Initial laboratories revealed hypoglycemia and primary hyperparathyroidism. A fasting test was positive after 3 hours of initiation. An abdominal CT Scan demonstrated a 28 × 27 mm mass in the pancreatic tail and bilateral nephrolithiasis. A distal pancreatectomy was done. After surgery, the patient persisted with hypoglycemic episodes that were managed with diazoxide and frequent feedings. A parathyroid Tc‐99 m MIBI scan with SPECT/CT imaging demonstrated two hot uptake lesions compatible with abnormally functioning parathyroid tissue. Surgical treatment was offered; however, the patient decided to postpone the procedure. Direct sequence analysis of MEN1 gene revealed heterozygosity for a pathogenic insertion c.1224_1225insGTCC (p.Cys409Valfs*41). DNA sequence analysis was done to six of his first‐degree relatives. A sister with clinical diagnosis of MEN1 and a pre‐symptomatic brother were positive for the same MEN1 variant. To our knowledge, this is the first report of a genetically confirmed case of MEN1 in our country and is the first report in literature of the c.1224_1225insGTCC variant related to a clinically affected family. [ABSTRACT FROM AUTHOR]

Hyperparathyroidism-jaw tumor syndrome is a rare disorder that is inherited in an autosomal dominant manner and predisposes to the development of parathyroid adenomas and carcinoma, ossifying jaw tumors, uterine neoplasms and renal cysts. It is caused by inactivating mutations in the gene CDC73 that it was first identified in 2002. The purpose of this narrative review is to highlight the genetic background of the syndrome and its clinical manifestations as well as to emphasize the significance of genetic testing in diagnosis from an early age. The clinical and familial features of the syndrome were collected by searching on electronic database PubMed/Medline using the MeSH terms "Hyperparathyroidism-jaw tumor syndrome" or "HPT-JT syndrome". 246 articles were returned of which, 44 were reviews and 59 case reports. Two nationwide retrospective studies were found. This article is focused mainly on data from the last decade, as there seems to be a better understanding of the genetic basis due to the evolution of DNA sequencing techniques. To date, there have been over 200 patients reported in approximately 50 families carrying a germline mutation of CDC73 gene, suggesting that there should be an augmented awareness of identifying both patients and their relatives. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia 2B (MEN2B) is a rare syndrome with prevalence estimated at approximately 0.2 per 100,000; it is caused by mutation of the RET proto-oncogene. MEN2B is characterized by early-onset medullary thyroid carcinoma (MTC), ganglioneuromatosis of the aerodigestive tract, marfanoid habitus, ophthalmologic abnormalities, and pheochromocytoma in adulthood. Mutations in the RyR1 gene manifest clinically in congenital myopathies and/or malignant hyperthermia susceptibility. We present a case of a 4-year-old boy with an accidentally detected RET and RyR1 mutations in the course of diagnostic approach of short stature and delayed motor development. Due to a poor and blurred clinical picture of MEN2B syndrome, accompanied by RyR1 mutation symptoms, the diagnostic path was extended. Our patient had no family history of MTC. In the imaging studies of the thyroid gland, no abnormalities were found, whereas the serum level of calcitonin was elevated to 34 pg/mL (N < 5.0). The patient qualified for total thyroidectomy, and the histopathological examination confirmed the diagnosis of MTC. The postoperative serum calcitonin level dropped to normal ranges. This case shows how new genetic diagnostic procedures could be crucial in accidentally diagnosing rare endocrine disease with atypical symptoms, giving an opportunity for relatively early intervention.

Abstract Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant disorder without a good genotype–phenotype correlation, characterized by tumor predisposition in the parathyroid gland, anterior pituitary, and pancreatic islet cells. Here, we describe a 37‐year‐old male with previous history of nephrolithiasis, with a 1‐year history of recurrent hypoglycemic episodes. Physical examination revealed the presence of two lipomas. Family history revealed primary hyperparathyroidism (PHPT), hyperprolactinemia, and multiple non‐functioning pancreatic neuroendocrine tumors. Initial laboratories revealed hypoglycemia and primary hyperparathyroidism. A fasting test was positive after 3 hours of initiation. An abdominal CT Scan demonstrated a 28 × 27 mm mass in the pancreatic tail and bilateral nephrolithiasis. A distal pancreatectomy was done. After surgery, the patient persisted with hypoglycemic episodes that were managed with diazoxide and frequent feedings. A parathyroid Tc‐99 m MIBI scan with SPECT/CT imaging demonstrated two hot uptake lesions compatible with abnormally functioning parathyroid tissue. Surgical treatment was offered; however, the patient decided to postpone the procedure. Direct sequence analysis of MEN1 gene revealed heterozygosity for a pathogenic insertion c.1224_1225insGTCC (p.Cys409Valfs*41). DNA sequence analysis was done to six of his first‐degree relatives. A sister with clinical diagnosis of MEN1 and a pre‐symptomatic brother were positive for the same MEN1 variant. To our knowledge, this is the first report of a genetically confirmed case of MEN1 in our country and is the first report in literature of the c.1224_1225insGTCC variant related to a clinically affected family.

Objective: To investigate the impact of musculoskeletal (MSK)‐related symptoms on the quality of life of patients with multiple endocrine neoplasia Type 2b (MEN2B). Design: An online survey was distributed by the Association for Multiple Endocrine Neoplasia Disorders (AMEND) to their members and worldwide via a social media group for MEN2B patients. Methods: The survey consisted of a detailed questionnaire analysing the MSK‐related symptoms and structural deformities of MEN2B patients and their impact on patient's lives. Participants: Forty‐eight participants completed the survey. Results: Participants reported several musculoskeletal complaints; the most prevalent being musculoskeletal weakness at 73% (n = 35) and pain 58% (n = 28). The median pain score was 7 (interquartile range [IQR]: 5–8) and the frequency of pain was daily in 44% (n = 15) and constant in 21% (n = 7). Structural complaints were common with 63% (n = 30) stating their physique was 'different' and 40% (n = 19) describing marfanoid body features. Spinal curvature and foot deformities were the commonest structural abnormalities with scoliosis 70% (n = 16) and pes cavus 63% (n = 22) prevailing. Dental problems were mentioned by 69% (n = 33) with interdental spacing being the most common complaint at 61% (n = 20). The musculoskeletal symptoms of MEN2B had a median impact of 6 (IQR: 3–9) on quality of life (QOL) with structural deformities 53% (n = 18) and pain 26% (n = 9) listed as having the highest impact. Poor MSK health affected exercise, work and mobility. Conclusions: We report a high prevalence of musculoskeletal‐related complaints in MEN2B which significantly affects QOL. This suggests a need to provide better holistic care including a multidisciplinary team with physiotherapist, orthopaedic and dental specialist input. [ABSTRACT FROM AUTHOR]

Les néoplasies endocriniennes multiples (NEM) sont des syndromes de prédisposition génétique aux tumeurs endocrines comprenant les NEM1, NEM2 et exceptionnellement les NEM4. Les NEM sont transmises par voie autosomique dominante avec une forte pénétrance. Une corrélation génotype/phénotype est classiquement retrouvée chez les patients ayant une NEM2 mais pas pour les NEM1. Les patients avec une NEM1, liée à une mutation inactivatrice du gène de la ménine , peuvent présenter : une hyperparathyroïdie primaire, un adénome hypophysaire, des tumeurs neuroendocrines (TNE) duodéno-pancréatiques et/ou bronchiques avec un surrisque de thymome, des tumeurs corticosurrénaliennes ; un sur-risque de cancer du sein et une atteinte cutanée caractéristique telle que les collagénomes, les lentiginomes et un sur-risque de cancer cutané. Ces patients nécessitent un suivi annuel au minimum. Le dépistage des enfants est proposé à partir de l'âge de 5 ans. Les patients avec une NEM2, liée à une mutation activatrice du proto-oncogène RET , présentent tous un carcinome médullaire thyroïdien (CMT) à un âge variable selon le génotype. Certains patients présentent un phéochromocytome (50 %) et une hyperparathyroïdie (20 %). Des formes pédiatriques avec un CMT agressif, une ganglioneuromatose et un syndrome marfanoïde existent (rare NEM2B). Certaines mutations sont associées à un risque de CMT agressif, justifiant une thyroïdectomie prophylactique avant l'âge de 6 mois. L'âge du dépistage génétique dépend du soustype de mutation chez le parent porteur de NEM2. Les NEM4, liées à une mutation du gène CDKN1B , sont rares, avec une pathogénie moins bien connue et leur suivi n'est pas bien codifié. Multiple endocrine neoplasia (MEN) are genetic predisposition syndromes to endocrine tumors including MEN1, MEN2 and exceptionally MEN4. MEN are transmitted in an autosomal dominant fashion with a high penetrance. Classically, there is no genotype/phenotype correlation for NEM1 whereas this is the case for NEM2. Patients with NEM1, linked to an inactivating mutation of the menin gene, may present with: primary hyperparathyroidism, pituitary adenoma, duodeno-pancreatic neuroendocrine tumors (NETs), bronchial tumors with an increased risk of thymoma, adrenal cortical tumors, an increased risk of breast cancer and characteristic skin involvement such as collagenomas, lentiginomas and an increased risk of skin cancer. These patients require at least annual follow-up. Screening of children is proposed from the age of 5 years. Patients with NEM2, linked to an activating mutation of the RET proto-oncogene, all present with medullary thyroid carcinoma (MTC) at a variable age depending on the genotype. Some patients present a pheochromocytoma (50 %) and hyperparathyroidism (20 %). Pediatric forms with aggressive CMT, ganglioneuromatosis and marfanoid syndrome exist (rare NEM2B). Some mutations are associated with a risk of aggressive CMT, justifying prophylactic thyroidectomy before 6 months of age. The age of genetic testing depends on the mutation subtype in the NEM2 parent. NEM4, related to a mutation in the CDKN1B gene, are rare, with a less well-known pathogenesis and their follow-up is not well codified. [ABSTRACT FROM AUTHOR]

Background/Aims Germline mutations of the rearranged during transfection (RET) gene cause multiple endocrine neoplasia type 2 (MEN2). About 85% of RET mutations in MEN2 occur in codon Cys634. The RET D631Y mutation has recently been discovered, and we have studied its molecular expression and clinical consequences. Methods We analyzed the clinical characteristics of a total of 34 D631Y variant MEN2 individuals from seven families. We also constructed wild-type and mutant C630Y, D631Y, and C634R/W expression vectors and investigated their effects on signaling pathways and ability to correct the phenotypes of RET mutant cells. Results The median ages at diagnosis of pheochromocytoma and medullary thyroid carcinoma (MTC) were higher in patients with RET D631Y variant MEN2 than in those with the C634R/W variant (49:53.5 years vs. 33.5:27 years, respectively), and the penetration of the D631Y mutation with respect to MTC was lower than that of the C634R/W mutation (32.3% vs. 90%). The effects of the mutant vectors on phosphorylation of RET signaling molecules and focus formation were significantly different from those of wild type, but there were no significant differences between the mutants. D631Y scored significantly higher for chemotaxis and wound healing than C630Y, but lower than C634R and C634W. Conclusions We suggest that the tumorigenic potential conferred by the D631Y mutation is lower than that conferred by the C634R/W mutation, but higher than that conferred by C630Y. Thus, the risk level of the RET D631Y variant appears to be higher than that of C630Y and lower than that of C634R/W.

Our objective was to overview the most recent data on primary hyperparathyroidism (PHP) in children and teenagers from a multidisciplinary perspective. Methods: narrative review based on full-length, English-language papers (from PubMed, between January 2020 and July 2023). Results: 48 papers (14 studies of ≥10 subjects/study, and 34 case reports/series of MEN1, followed by CDC73, CASR, RET, and CDKN1B, as well as one case of VHL. Symptomatic PHP: 70–100% of all cases. Asymptomatic PHP: 60% of genetic PHP cases. Renal involvement: 10.5% of a cohort with genetic PHP, 71% of sporadic PHP cases; 50% (in a cohort with a mean age of 16.7), 29% (in a cohort with a mean age of 15.2); 0% (in infancy) to 50–62% (in teenagers). Bone anomalies: 83% of the children in one study and 62% of those in two other studies. Gastrointestinal issues: 40% of one cohort, but the data are heterogeneous. Cure rate through parathyroidectomy: 97–98%. Recurrent PHP: 2% of sporadic PHP cases and 38% of familial PHP cases. Hungry bone syndrome: maximum rate of 34–40%. Case reports identified another 7/41 subjects with the same post-parathyroidectomy condition; a potential connection with ectopic presentation or brown tumors is suggested, but there are limited data. Minimally invasive thoracoscopic approaches for ectopic tumors seemed safe. The current level of statistical evidence on pediatric PHP qualifies our study- and case-sample-based analysis (n = 48, N = 534) as one of the largest of its kind. Awareness of PHP is the key factor to benefit our young patients.

Multiple endocrine neoplasia (MEN) is a group of heterogenous syndromes characterized by the occurrence of two or more endocrine gland tumors in a patient or related individuals in the same family. They are inherited in an autosomal dominant fashion and are highly penetrant. There are three types of MEN syndromes: MEN type 1 (MEN1), MEN type 2 (MEN2), and MEN type 4 (MEN4). MEN2 is further divided into MEN2A, MEN2B (formerly known MEN3), and familial medullary thyroid carcinoma (FMTC). Although MEN syndromes are rare, it is crucial to identify individuals at risk for potentially life-threatening neoplasias. This review article provides an update on each MEN syndrome, its genetics, diagnosis, and management in children.

Insulinoma is a rare pancreatic neuroendocrine tumour (PNET) with an incidence rate of 4 per million population, and the most common cause of hypoglycaemia due to endogenous hyperinsulinism. We present the story of a 61-year-old male, who was extensively evaluated at many hospitals for his symptoms of giddiness, uneasiness and recurrent black outs for the last 3 months, his symptoms disappearing with a carbohydrate rich meal or sweets. Random sugar and fasting sugar values noted were low, with elevated insulin and C-peptide levels. Diagnosis of insulinoma was confirmed by a DOTA PET scan involving the tail of the pancreas and then surgically removed. Early detection is crucial for early surgery to allay symptoms. We describe our diagnostic and treatment plan with reference to previously published reports.