Multiple Endocrine Neoplasia Type Research Articles

7109 "My Stomach hurts": A Rare Case of Adrenal Cortical Carcinoma

Abstract Disclosure: R.C. Attah: None. I. Sirisena: None. Pheochromocytoma/Paragangliomas are rare neurogenic tumors that arise from chromaffin cells present in the adrenal medulla or extra-adrenal paraganglia, these cells produce catecholamines. Typically, these tumors are discovered as incidentalomas. They can be hereditary as seen in genetic syndromes like multiple endocrine neoplasia type 2A or 2B, neurofibromatosis type 1 or Von Hippel Lindau syndrome but can occur sporadically. Patients typically present with hormonal hypersecretion signs or symptoms like abdominal pain, episodic headaches, sweating, hypertension and tachycardia, but some patients are asymptomatic. Patient is a 37-year-old female with past medical history of hypertension, type 2 diabetes mellitus and fatty liver who presented to the ED with abdominal pain for a few weeks. On arrival, her vitals were BP 205/124, HR 102, RR 14 and SpO2 100% on room air. CT abdomen was obtained which showed a 7.6 x 4.7 x 5.7 cm mass replacing left adrenal gland with small left retroperitoneal hemorrhage worrisome for adrenal cortical carcinoma, metastatic disease or pheochromocytoma. Hormonal workup revealed elevated 24-hr urine cortisol 124.2mcg (ref 4.0-50.0mcg/24h), normal aldosterone/renin ratio 10.63ng/dL (ref <30ng/dl), failed low dose dexamethasone suppression test with post-dex AM cortisol 7.20ug/dL (ref <1.8ug/dL), slightly elevated serum total catecholamine 1256pg/mL (242-1125 pg/mL), norepinephrine 1155pg/mL (ref 217-1109 pg/mL), total metanephrine and normetanephrine 341pg/mL (reg <205 pg/mL), normetanephrine 244.1 (ref <210.1pg/mL), elevated 24-hr urine normetanephrine 700ug/L (ref 131-612ug/L), metanephrine 136ug/L (ref 36-209ug/L) and DHEA-s level 285ug/dl (ref 23-266ug/dL). Due to elevation in cortisol, adrenal cortical carcinoma was suspected as these tumors are frequently associated with cortisol secretion. However, pheochromocytoma with co-secretion of ACTH could not be excluded. She was started on doxazosin for alpha blockade and eventually started on beta blockade with Metoprolol. She underwent a left adrenalectomy and was started on steroid taper post-op due to concern of cortisol co-secretion. Surgical pathology was positive for Left adrenal malignant pheochromocytoma and ganglioneuroma. Genetic panel was negative with no mutation identified in the 54 gene Hereditary paraganglioma-pheochromocytoma panel. This patient had a large adrenal tumor (>4cm mass) but mildly elevated catecholamines which could have led to misdiagnosis as her catecholamine levels were less than 2-3x ULN which is unusual for pheochromocytomas. Roughly 25% of people with pheochromocytoma are undiagnosed throughout their lifespan. This condition can be life-threatening, hence early diagnosis and intervention can be lifesaving. Prognosis of malignant pheochromocytoma is dependent on tumor size, presence of SDHB gene mutation or visceral metastases. Presentation: 6/1/2024

The Long-Term Cure of Patients With Hereditary Medullary Thyroid Carcinoma: 40 Years of Follow-Up in a Single Center.

The cure rate of patients with hereditary medullary thyroid carcionoma (MTC) can be decisively improved by screening for elevated calcitonin (Ctn) levels and RET gene mutations in patients from families affected by multiple endocrine neoplasia type 2 (MEN2), followed by prophylactic thyroidectomy in persons with mutated RET genes. In this long-term observational study, we investigated whether postoperative cures are indeed maintained decades after the procedure. From 1979 to 2021, 277 patients with MEN2 who underwent thyroidectomy were observed postoperatively for 14.4 ± 10.3 years (mean, standard deviation). They were classified as either cured or not cured depending on the last measured serum Ctn level (cured, Ctn < 10 pg/mL or < 2 pg/mL; not cured, Ctn ≥ 10 pg/mL). Depending on their RET mutation status, they were categorized as moderate, high, or highest risk (121, 130, and 26 patients, respectively). 154 patients (55.6%) obtained a long-term cure (Ctn <10 pg/mL). The median age at surgery was 27, 14, and 4 years in patients at moderate, high, and highest risk. All 52 patients who had undergone prophylactic thyroidectomy before the age of 6 years, 9 years, or 6 months had a Ctn level below 2 pg/mL and were cured at the end of the follow-up period. In a multivariable analysis, prognostic factors for a long-term cure were a lower tumor stage and, by tendency, classification as belonging to the moderate as opposed to the highest-risk group. In patients receiving an early diagnosis of MEN2 via family screening, prophylactic thyroidectomy taking into account the RET mutation risk group can achieve a long-term cure of MTC with undetectable serum Ctn levels.

Living with a RET gene mutation: patient perspectives.

Multiple endocrine neoplasia type 2 (MEN2) is the collective term for 2 distinct types of autosomal dominantly inherited neuroendocrine neoplasm (NEN) syndromes (Barakat, 2004); MEN2A and MEN 2B (or MEN3). MEN2 is characterised by medullary thyroid cancer (99%) and phaeochromocytoma (50%) but also other conditions according to specific genotype. MEN2A also includes a 25% risk of developing parathyroid hyperplasia and is now recognised as 4 separate syndromes: Classic MEN2A, MEN2A with cutaneous lichen amyloidosis (CLA), MEN2A with Hirschsprung's disease (HD) and Familial MTC (Wells, 2015). MEN2B accounts for around 5% of all MEN2 cases and predisposes patients to diffuse intestinal ganglioneuromatosis (Goncharova, 2020), mucosal neuromas, and musculoskeletal abnormalities (Henderson, 2022). MEN2 is autosomal dominantly inherited meaning that several generations in a single family may be affected by the same syndrome. We present a mini review of 4 case studies (x2 MEN2A, x2 MEN2B) that illustrate the advantages of RET testing, as well as some of the likely obstacles that must be overcome to receive a diagnosis of MEN2A or MEN2B. In addition, despite improved genotype/phenotype correlation in MEN2, we highlight that not all cases are 'typical' which emphasises the need for all MEN2 patients to be cared for in a centre of expertise and experience. Some of our case study patients or parents also took this opportunity to personally tell us more about their lives with MEN2, illustrating the need for more research into the psychosocial impact of these hereditary diseases.

Cellular Mechanisms of RET Receptor Dysfunction in Multiple Endocrine Neoplasia 2.

REarranged during Transfection (RET) is a developmentally important receptor tyrosine kinase that has been identified as an oncogenic driver in a number of cancers. Activating RET point-mutations give rise to the inherited cancer syndrome Multiple Endocrine Neoplasia type 2 (MEN2), characterized by medullary thyroid carcinoma. There are two MEN2 subtypes, MEN2A and MEN2B, that differ in tumour aggressiveness and the associated constellation of other disease features, which are caused by distinct patterns of RET amino acid substitution mutations. MEN2A-RET mutations affecting extracellular cysteine residues promote ligand independent dimerization and constitutive RET activity, while MEN2B is caused by a single amino acid change in the tyrosine kinase domain of RET, releasing autoinhibition and producing a more active MEN2B-RET kinase that can promote signalling as monomers or dimers in the absence of ligand. These mutations cause intrinsic biochemical changes in RET structure and activation but also trigger extrinsic effects that alter RET cellular location, interactions and mechanisms of downregulation that can prolong or mislocate RET activity, changing or enhancing functional outcomes. Together, changes in specific combinations of RET-mediated effects associated with different mutations give rise to the distinct MEN2 disease phenotypes. Here, we discuss the current understanding of the intrinsic and extrinsic characteristics of RET MEN2A cysteine and MEN2B mutants and how these contribute to transforming cellular processes and to differences in tumour progression and disease aggressiveness.

Genotype/phenotype correlations in multiple endocrine neoplasia type 2.

Multiple endocrine neoplasia type 2 (MEN 2) is a rare hereditary endocrine tumour syndrome caused by mutations in the rearranged during transfection (RET) gene. MEN 2 is divided into two main entities, MEN 2A and MEN2B, both of which present with medullary thyroid cancer (MTC) in approximately 100% of cases and pheochromocytoma in 50% of cases. Specific RET mutations are associated with a risk of early onset of MTC, from 1 year of age (highest risk) to 5 years of age (high risk). This risk defines the optimal timing for thyroidectomy, ideally at an age when the disease has not spread. This is the most important genotype-phenotype correlation observed in MEN 2. Specific RET mutations also define the penetrance of pheochromocytoma. However, despite the presence of these highest/high risk variants, some patients unexpectedly present with non-aggressive MTC or never present with pheochromocytoma, suggesting that factors other than the major RET variant may modify the natural history and genotype-phenotype correlations. Improving our understanding of the genotype-phenotype correlations would allow individualizing the management and follow-up of patients with MEN 2. The aim of this brief review is to discuss the main genotype-phenotype correlations in MEN 2 and the potential factors that might influence these correlations.

12486 Clinical Manifestations And Mortality Outcomes Of Multiple Endocrine Neoplasia Type 2 Patients With Medullary Thyroid Cancer In Korea Using The National Health Insurance Service Database

12486 Clinical Manifestations And Mortality Outcomes Of Multiple Endocrine Neoplasia Type 2 Patients With Medullary Thyroid Cancer In Korea Using The National Health Insurance Service Database

12486 Clinical Manifestations And Mortality Outcomes Of Multiple Endocrine Neoplasia Type 2 Patients With Medullary Thyroid Cancer In Korea Using The National Health Insurance Service Database

12486 Clinical Manifestations And Mortality Outcomes Of Multiple Endocrine Neoplasia Type 2 Patients With Medullary Thyroid Cancer In Korea Using The National Health Insurance Service Database

La prise en charge des cancers médullaires de la thyroïde en 2024

MANAGING MEDULLARY THYROID CARCINOMA IN 2024: Medullary thyroid carcinoma is a rare neuroendocrine thyroid cancer with a heterogeneous prognosis which has the particularity of being associated with a RET gene mutation, germline in 20-25% of cases in the context of multiple endocrine neoplasia type 2 (NEM2), and somatic in 70% of sporadic cases. It is often diagnosed on a thyroid nodule or in the context of genetic screening. Calcitonin is a biological marker, used for diagnosis, monitoring of therapeutic response and prognostic evaluation. The only curative treatment is surgery for localized disease. The extent must be carefully assessed, particularly in terms of calcitonin levels and imaging, and carried out by an expert surgeon. The prognosis of locally advanced or metastatic disease is highly heterogeneous. Histological factors, such as high grade, or biological factors, such as calcitonin doubling time, can help assess prognosis. The development of multi-kinase inhibitors cabonzantinib and vandetanib, and RET-targeted inhibitors selpercatinib, has completely changed the therapeutic arsenal for advanced disease, but their prescription is reserved to progressive disease with high tumor volume or to symptomatic disease inaccessible to local treatment in expert centers from the ENDOCAN-TUTHYREF network. Active surveillance is the alternative of choice for slowly progressing disease.

Diagnosis and management of pituitary adenomas in children and adolescents.

Pituitary adenomas (PAs)-also now called pituitary neuroendocrine tumours or Pit-NETS-are rare in children and adolescents and exceptional below the age of 10. Most evidence-based high-quality data are derived from larger studies in adult patients. We will review recent knowledge on the epidemiology, clinical features, diagnosis, and treatment modalities of the different types of pituitary adenomas diagnosed in children and adolescents, emphasizing the many reasons why these cases should be discussed within pituitary-specific multidisciplinary teams with experts from both paediatric and adult practice. Paediatric PA presents multiple peculiarities that may challenge their adequate management. They are overall proportionally larger and more aggressive than in adults, with potential mass effects including hypopituitarism. Hormonal hypersecretion is frequent, resulting in clinical syndromes affecting normal growth and pubertal development. Prolactinomas represent the most frequent subtype of PA found during childhood, followed by adrenocorticotropin (ACTH) and growth hormone (GH)-secreting adenomas, while clinically non-functioning adenomas are exceptionally diagnosed before the age of 16. The occurrence of a pituitary tumour in a young individual should also prompt genetic testing in each case, searching for either germline mutations in one of the known genes that may drive inherited/familial PA (such as the multiple endocrine neoplasia type 1 or MEN1 gene, or the aryl hydrocarbon receptor interacting protein or AIP gene), or for a mosaic activating mutation of GNAS as found in the McCune-Albright syndrome.

Characteristics of Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 2A

Characteristics of Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 2A

Exploring Multiple Endocrine Neoplasia Type 2B: Key Findings from a Case Report

Multiple endocrine neoplasia type 2B (MEN 2B) is an autosomal dominant syndrome primarily caused by the germline M918T RET mutation. It is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PC), and non-endocrine features. Symptoms depend on the glandular elements present. The initial diagnosis of MEN 2B is relatively late, and the diagnosis by non-endocrine components is extremely weak. The initial management consists of a total thyroidectomy with dissection of the lymph nodes. If PC is present, its treatment is surgical removal, which should be performed before thyroidectomy for MTC. The prognosis of MTC in MEN 2B depends on the stage at diagnosis, and only early diagnosis and intervention offer a chance of cure. It is necessary to underline the need to treat the extra-endocrine signs in these patients. We present below a case of MEN 2B who consulted late for a cervical tumor and morphological abnormalities of the lips and tongue.

Menin in Cancer.

The protein menin is encoded by the MEN1 gene and primarily serves as a nuclear scaffold protein, regulating gene expression through its interaction with and regulation of chromatin modifiers and transcription factors. While the scope of menin's functions continues to expand, one area of growing investigation is the role of menin in cancer. Menin is increasingly recognized for its dual function as either a tumor suppressor or a tumor promoter in a highly tumor-dependent and context-specific manner. While menin serves as a suppressor of neuroendocrine tumor growth, as seen in the cancer risk syndrome multiple endocrine neoplasia type 1 (MEN1) syndrome caused by pathogenic germline variants in MEN1, recent data demonstrate that menin also suppresses cholangiocarcinoma, pancreatic ductal adenocarcinoma, gastric adenocarcinoma, lung adenocarcinoma, and melanoma. On the other hand, menin can also serve as a tumor promoter in leukemia, colorectal cancer, ovarian and endometrial cancers, Ewing sarcoma, and gliomas. Moreover, menin can either suppress or promote tumorigenesis in the breast and prostate depending on hormone receptor status and may also have mixed roles in hepatocellular carcinoma. Here, we review the rapidly expanding literature on the role and function of menin across a broad array of different cancer types, outlining tumor-specific differences in menin's function and mechanism of action, as well as identifying its therapeutic potential and highlighting areas for future investigation.

Childhood Multiple Endocrine Neoplasia (MEN) Syndromes: Genetics, Clinical Heterogeneity and Modifying Genes.

Multiple endocrine neoplasia (MEN) syndromes are part of a spectrum of clinically well-defined tumor syndromes ultimately characterized by histologically similar tumors arising in patients and families with mutations in one of the following four genes: MEN1, RET, CDKN1B, and MAX. The high level of genetic and phenotypic heterogeneity has been linked to phenocopies and modifying genes, as well as unknown mechanisms that might be investigated in the future based on preclinical and translational considerations. MEN1, also known as Wermer's syndrome (OMIM *131100), is an autosomal dominant syndrome codifying for the most frequent MEN syndrome showing high penetrance due to mutations in the MEN1 gene; nevertheless, clinical manifestations vary among patients in terms of tumor localization, age of onset, and clinical aggressiveness/severity, even within the same families. This has been linked to the effect of modifying genes, as described in the review. MEN 2-2b-4 and 5 also show remarkable clinical heterogeneity. The traditional view of genetically predisposing monogenic or multifactorial disorders is no longer valid, and mandates a change in scientific focus. Phenotypes are indeed rarely consistent across genetic backgrounds and environments. In the future, understanding factors and genetic variants that control cellular functions and the expression of disease genes should provide insights into fundamental disease processes, providing implications for counseling and therapeutic and prophylactic possibilities.

Primary hyperparathyroidism in multiple endocrine neoplasia type 1 (MEN1): the northern ireland (NI) experience

Primary hyperparathyroidism in multiple endocrine neoplasia type 1 (MEN1): the northern ireland (NI) experience

Transformation of non-functioning pancreatic neuroendocrine tumours into insulinomas in multiple endocrine neoplasia type 1: a case report

Transformation of non-functioning pancreatic neuroendocrine tumours into insulinomas in multiple endocrine neoplasia type 1: a case report

Thyroid Malignancy and Cutaneous Lichen Amyloidosis: Key Points Amid RET Pathogenic Variants in Medullary Thyroid Cancer/Multiple Endocrine Neoplasia Type 2 (MEN2).

We aimed to provide an updated narrative review with respect to the RET pathogenic variants and their implications at the clinical and molecular level in the diagnosis of medullary thyroid cancer (MTC)/multiple endocrine neoplasia (MEN) type 2, particularly with respect to the presence of cutaneous lichen amyloidosis (CLA). We searched English-language, in extenso original articles with no timeline nor study design restriction that were published on PubMed. A traditional interplay stands for CLA and MTC in MEN2 (not MEN3) confirmation. While the connection has been reported for more than three decades, there is still a large gap in understanding and addressing it. The majority of patients with MEN2A-CLA have RET pathogenic variants at codon 634; hence, it suggests an involvement of this specific cysteine residue in both disorders (most data agree that one-third of C634-positive subjects have CLA, but the ranges are between 9% and 50%). Females seem more prone to MEN2-CLA than males. Non-C634 germline RET pathogenic variants included (at a low level of statistical evidence) the following: RET V804M mutation in exon 14 for MTC-CLA (CLA at upper back); RET S891A mutation in exon 15 binding OSMR variant G513D (familial MTC and CLA comprising the lower legs to thighs, upper back, shoulders, arms, and forearms); and C611Y (CLA at interscapular region), respectively. Typically, CLA is detected at an early age (from childhood until young adulthood) before the actual MTC identification unless RET screening protocols are already applied. The time frame between CLA diagnosis and the identification of RET pathogenic variants was between 5 and 60 years according to one study. The same RET mutation in one family is not necessarily associated with the same CLA presentation. In MTC/MEN2 subjects, the most affected CLA area was the scapular region of the upper back. Alternatively, another hypothesis highlighted the fact that CLA is secondary to long-term prurit/notalgia paresthetica (NP) in MTC/MEN2. OSMR p. G513D may play a role in modifying the evolutionary processes of CLA in subjects co-harboring RET mutations (further studies are necessary to sustain this aspect). Awareness in CLA-positive patients is essential, including the decision of RET testing in selected cases.

Laryngeal Neuromas in a 5-Year-Old With MEN2B: A Case Report and Literature Review.

Multiple endocrine neoplasia type 2B (MEN2B) syndrome is a rare genetic disorder primarily driven by mutations in the RET proto-oncogene. MEN2B exhibits diverse symptoms affecting multiple organ systems, with mucosal neuromas being a prominent feature. These benign tumors contribute to the syndrome's clinical variability, alongside medullary thyroid carcinoma and pheochromocytoma. The article presents a case study of a young girl diagnosed with MEN2B, complicated by laryngeal neuromas leading to respiratory distress post-thyroidectomy. Laryngeal neuromas are exceedingly rare, underscoring the importance of recognizing such manifestations for proper airway management, especially during surgical interventions. Despite its rarity, MEN2B presents significant clinical challenges, requiring early detection, genetic counseling, and multidisciplinary management for improved outcomes. Clinicians must remain vigilant for rare manifestations like laryngeal neuromas to prevent serious complications, particularly during surgical procedures.

Pituitary Neuroendocrine Tumors in Multiple Endocrine Neoplasia.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant disorder characterized by tumors of the pituitary, parathyroid, and endocrine-gastrointestinal tract. Pituitary neuroendocrine tumors (PitNETs) occur in about 40% of MEN1 cases, with 10% being the first manifestation. Recent studies show a slight female predominance, with microPitNETs (<1 cm) being more common than macroPitNETs (>1 cm). Functional PitNETs (FPitNETs) are more frequent than non-functional ones (36% to 48%), with prolactinomas being the most common FPitNETs. MEN1-associated PitNETs are often plurihormonal, larger, and more invasive compared to sporadic types, though patient age and FPitNET proportions are similar. MEN1 mutation-negative patients tend to have larger, symptomatic PitNETs at diagnosis. Six patients with MEN1 have been reported to have pituitary carcinomas, including a mutation- negative patient. Treatment approach between PitNETs in MEN1 and sporadic types appears to be similar. PitNETs also occur in MEN4, but their epidemiology is less understood. In patients with a MEN1-like phenotype and negative genetic testing, MEN4 should be considered.

Clues for Early Diagnosis of MEN2B Syndrome Before Medullary Thyroid Carcinoma.

Early onset medullary thyroid carcinoma, later pheochromocytomas, and nonspecific extra-endocrine features (hypermobility and persistent constipation) are part of the clinical phenotype of Multiple Endocrine Neoplasia type 2B (MEN2B). A de novo pathogenic M918T variant in the rearranged during transfection proto-oncogene is usually identified. Affected children are often seen by multiple clinicians over a long period before consideration of a diagnosis of MEN2B, with metastatic medullary thyroid carcinoma often the precipitator. We describe the clinical presentation and course of 5 children ultimately diagnosed with MEN2B in New South Wales and the Australian Capital Territory, Australia between 1989 and 2021. All cases had intestinal ganglioneuromatosis that could have prompted an earlier diagnosis. Population wide newborn genomic screening for rare diseases is on the horizon. We propose that MEN2B genomic screening should be included in newborn screening programs and that careful exclusion of intestinal ganglioneuromatosis would allow earlier identification leading to improved clinical outcomes.

Multiple Endocrine Neoplasia Type 1.

Multiple endocrine neoplasia type 1 (MEN1) is a rare genetic disease of autosomal dominant inheritance, with an estimated prevalence of 3-20/100 000. Its main feature is neuroendocrine neoplasia in the parathyroid glands, the endocrine pancreas, the duodenum, and the pituitary gland. In this article, we review the diagnostic and therapeutic options for MEN1-associated tumors. We present an analysis and evaluation of retrospective case studies retrieved from PubMed, guidelines from Germany and abroad, and our own experience. The disease is caused by mutations in the MEN1 gene. Mutation carriers should participate in a regular, specialized screening program from their twenties onward. The early diagnosis and individualized treatment of MEN1-associated tumors can prevent the development of life-threatening hormonal syndromes and prolong the expected life span of MEN1 patients from 55 to 70 years, as well as improving their quality of life. Surgical treatment is based on the location, size, growth dynamics, and functional activity of the tumors. The evidence for treatment strategies is derived from retrospective studies only (level III evidence) and the optimal treatment is often a matter of debate. This is a further reason for treatment in specialized centers. MEN1 is a rare disease, and, consequently, the evidence base for its treatment is limited. Carriers of disease-causing mutations in the MEN1 gene should be cared for in specialized interdisciplinary centers, so that any appreciable tumor growth or hormonal activity can be detected early and organ-sparing treatment can be provided.