Multiple Endocrine Neoplasia Research Articles

Developing Dynamic Structure-Based Pharmacophore and ML-Trained QSAR Models for the Discovery of Novel Resistance-Free RET Tyrosine Kinase Inhibitors Through Extensive MD Trajectories and NRI Analysis.

Activation of RET tyrosine kinase plays a critical role in the pathogenesis of various cancers, including non-small cell lung cancer, papillary thyroid cancers, multiple endocrine neoplasia type 2A and 2B (MEN2A, MEN2B), and familial medullary thyroid cancer. Gene fusions and point mutations in the RET proto-oncogene result in constitutive activation of RET signaling pathways. Consequently, developing effective inhibitors to target RET is of utmost importance. Small molecules have shown promise as inhibitors by binding to the kinase domain of RET and blocking its enzymatic activity. However, the emergence of resistance due to single amino acid changes poses a significant challenge. In this study, a structure-based dynamic pharmacophore-driven approach using E-pharmacophore modeling from molecular dynamics trajectories is proposed to select low-energy favorable hypotheses, and ML-trained QSAR models to predict pIC50 values of compounds. For this aim, extensive small molecule libraries were screened using developed ligand-based models, and potent compounds that are capable of inhibiting RET activation were proposed.

Genotype-specific development of MEN 2 constituent components in 683 RET carriers.

The age-specific development of the 3 constituent components of multiple endocrine neoplasia type 2 (MEN 2) is incompletely characterized for many of the >30 causative rearranged during transfection (RET) mutations, which this genetic association study aimed to specify. Included in the study were 683 carriers of heterogeneous RET germline mutations: 53 carriers with 1 highest-risk mutation (codon 918); 240 carriers with 8 different high-risk mutations (codon 634); 176 carriers with 16 different intermediate-risk mutations (codon 609, 611, 618, 620 or 630); and 214 carriers with 6 different low-risk mutations (codon 768, 790, 804 or 891). There was a strong genotype-specific development of MEN 2 constituent components, with distinct age gradients from C cell disease to node-negative MTC, from node-negative to node-positive MTC, from node-positive MTC to pheochromocytoma, and from pheochromocytoma to primary hyperparathyroidism. Primary hyperparathyroidism was not observed among the 53 MEN 2B patients who carried highest-risk mutations (age range 0.5-50 yrs.), of whom no more than 12 (23%) and 3 (6%) carriers were older than age 30 yrs. and 35 yrs., respectively. The age-specific development of MTC differed significantly between the 4 RET risk categories, whereas the age-specific development of pheochromocytoma differed significantly only between the 2 strongest RET risk categories. No significant differences were noted in the development of primary hyperparathyroidism. These findings delineate age-specific disease manifestation corridors for the 3 constituent components of MEN 2 by RET genotype. These corridors are useful for initial risk assessment and organ-specific surveillance of newly identified RET carriers going forward.

Multiple endocrine neoplasia type 2B diagnosed after small intestinal volvulus with progressive megacolon in an adolescent

Multiple endocrine neoplasia type 2B is a rare autosomal dominant disease characterized by the presence of medullary thyroid carcinoma, pheochromocytoma, Marfan-like fatigue, a peculiar face with thickening of the lips, mucosal neuromas on the lips and tongue, and gastrointestinal phenomena. Most patients harbor pathological variants of the RET gene. Herein, we present the first case of a 14 year-old boy who experienced small intestinal volvulus along with a megacolon, and he was diagnosed with multiple endocrine neoplasia type 2B. The patient complained of constipation since he was 2 years old and slowly progressive abdominal distension at school age. At 14 years of age, he presented with remarkable megacolon mimicking Hirschsprung’s disease and complicated with small intestinal volvulus. The volvulus was successfully repaired, and the particularly dilated transverse colon was resected following a rectal biopsy. Histopathological evaluation of the resected transverse colon revealed to be compatible with ganglioneuromatosis. After emergency surgery, the patient was diagnosed with multiple endocrine neoplasia type 2B with medullary thyroid carcinoma, and a de novo variant of RET was confirmed. Gastroenterologists should consider it when treating patients with constipation, especially those with megacolon. Therefore, timely diagnosis may lead to appropriate treatment of medullary thyroid carcinoma and improve mortality.

Syndromic MEN1 Parathyroid Adenomas Consist of Both Subclonal Nodules and Clonally Independent Tumors

Abstract Background Primary hyperparathyroidism with parathyroid tumors is a characteristic presentation in Multiple Endocrine Neoplasia Type 1 (MEN1), historically referred to as "primary hyperplasia." The question of whether these tumors signify a multi-glandular clonal disorder or hyperplasia remains inconclusive. Loss of Menin protein expression serves as a reliable surrogate marker for biallelic inactivation and indicates a mutation in the MEN1 gene. The cyclin-dependent kinase inhibitor 1B (CDKN1B) gene, associated with MEN4, encodes the p27 protein, whose expression is inadequately explored in the context of syndromic MEN1. Aims The aim was to explore the molecular basis of syndromic MEN1 parathyroid adenomas, identifying hyperplasia, multiple independent clones, and the extent of Menin loss. Additionally, p27 expression was assessed to evaluate its potential in indicating a germline mutation, especially in distinguishing MEN4 as a clinical alternative to MEN1. Methods In this investigation, we examined histomorphology and protein expression of Menin and p27 in parathyroid adenomas from 25 patients in two independent, well-characterized MEN1 cohorts. Loss of heterozygosity (LOH) patterns were evaluated using fluorescence in situ hybridization (FISH) in one MEN1-associated parathyroid adenoma. Furthermore, next-generation sequencing (NGS) was conducted on eleven nodules from four MEN1 patients. Results Morphologically, the majority of MEN1 adenomas displayed multiple distinct nodules, characterized by predominantly lost Menin expression and reduced p27 protein expression. FISH analysis indicated that most nodules exhibited MEN1 loss, with or without centromere 11 loss. NGS demonstrated both subclonal evolution and the existence of clonally unrelated tumors. Conclusion Syndromic MEN1 parathyroid adenomas, therefore, consist of multiple clones with subclones, aligning with the current framework of the novel WHO classification of parathyroid tumors (2022). The observed loss of p27 expression in a significant fraction of MEN1 parathyroids emphasizes the need for caution when inferring MEN4 solely based on p27 expression.

A comparative analysis of surgically excised hereditary and sporadic pheochromocytomas: Insights from a single-center experience.

Pheochromocytoma is a tumor that usually originating from adrenal medullary chromaffin cells and producing one or more catecholamines, can manifest as hereditary or sporadic. While the majority pheochromocytomas are sporadic, hereditary forms are often associated with genetic syndromes such as von Hippel-Lindau, multiple endocrine neoplasia type 2, and neurofibromatosis type 1. This study aims to analyze data from our series of surgically excited pheochromocytoma patients and compare the characteristics between hereditary and sporadic cases. We retrospectively evaluated 33 diagnosed pheochromocytoma patients, documenting clinical features, surgical complications, and tumor characteristics in both hereditary and sporadic cases. Among the patients, 21% (7 individuals) had hereditary pheochromocytoma, while 79% (26 individuals) had sporadic cases. During diagnosis, hereditary pheochromocytoma patients exhibited a significantly lower mean age compared to the sporadic group (26.4 ± 9.9 years vs. 50.4 ± 14.0 years; p < 0.001). The maximum tumor size was also lower in hereditary cases compared to sporadic cases (p = 0.004). Adrenal tumor localization analysis showed that 63.6% were right-sided, 24.2% were left-sided, and 12.1% were bilateral. Laboratory analysis revealed significantly higher urinary norepinephrine levels in hereditary pheochromocytoma patients (p = 0.021). Our findings suggest that hereditary pheochromocytoma cases are characterized by a younger age at diagnosis, smaller tumor size, and a higher prevalence of multiple bilateral adrenal adenomas. We recommend genetic testing for all pheochromocytoma patients, particularly those with early-onset disease and bilateral adrenal tumors.

Appendiceal NET in an 18-year-old woman, the youngest case of MEN4 with neuroendocrine manifestation: case report and review of the current literature

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominantly inherited syndrome. It is caused by loss-of-function mutation of the MEN1 gene, and characterized by variable association of primary hyperparathyroidism, pituitary adenomas and neuroendocrine tumours (NETs). Up to 3% of MEN1-like syndromes present a loss-of-function mutation in the tumour-suppressor gene CDKN1B, and therefore constitute MEN4 syndrome. Data on MEN4 clinical behaviour, penetrance and associated manifestations are still incomplete. We report the case of a young woman diagnosed with a rare NET G1 of the appendix at the age of 18 years. Genetic analysis revealed a germline missense mutation (c.397C&gt;A), present in heterozygosity, of codon 133 in the CDKN1B gene. To date only 26 mutations of CDKN1B have been described in association with a MEN4 phenotype. Subsequently, the patient’s sister, father and paternal uncle were found to be carriers of the same mutation but showed no clinical or biochemical signs of disease. This is currently the youngest case of MEN4 with a gastrointestinal tract NET reported in the literature, and the first with appendiceal involvement. Despite the absence of disease within the proband’s family, ongoing screening would seem to be warranted, along the lines of that described by other authors for MEN1 patients. KEY WORDS: MEN4, CDKN1B mutations, youngest case of NET in MEN4, appendiceal NET, MEN4 review.

Facial Features of Hereditary Cancer Predisposition.

In the age of telehealth medicine, an individual's facial features may provide the only physical clues signaling the presence of a heritable cancer predisposition syndrome. These syndromes include APC-associated polyposis, Birt-Hogg-Dubé syndrome, CYLD cutaneous syndrome, hereditary leiomyomatosis and renal cell cancer, multiple endocrine neoplasia, neurofibromatosis type 1, Peutz-Jeghers syndrome, PTEN hamartoma tumor syndrome, and tuberous sclerosis complex 1 and 2, among others. Correctly identifying characteristic features is important for genetic and nongenetic specialists as early detection can enable prompt intervention, improving patient outcomes. Advancements in the availability of genetic testing allow patients and their relatives to have more information about their genetic risk profile than before. These changes in clinical pathways, combined with improvements in screening and risk-reducing treatment, highlight the need to outline the cutaneous and morphologic features of high-risk cancer syndromes for clinicians. In this review, we describe the important facial features of hereditary cancer predisposition, with emphasis on diagnosis, cutaneous and extracutaneous manifestations, and screening.

Type 1 multiple endocrine neoplasia syndrome - saved by the somatostatin receptors

Type 1 multiple endocrine neoplasia syndrome - saved by the somatostatin receptors

Clinical presentation of sporadic and familial medullary thyroid carcinoma: is there a real difference?

Clinical presentation of sporadic and familial medullary thyroid carcinoma: is there a real difference?

Patient perception of unmet needs for multiple endocrine neoplasia (MEN) in germany

Patient perception of unmet needs for multiple endocrine neoplasia (MEN) in germany

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

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

Spontaneous and treatment-related changes in calcitonin doubling rate of medullary thyroid cancer. Long-term experience in a patient with multiple endocrine neoplasia type 2B

Spontaneous and treatment-related changes in calcitonin doubling rate of medullary thyroid cancer. Long-term experience in a patient with multiple endocrine neoplasia type 2B

Multiple endocrine neoplasia type 1: diverse clinical presentations and diagnostic challenges

Multiple endocrine neoplasia type 1: diverse clinical presentations and diagnostic challenges

Multiple endocrine neoplasia type 1 in children and adolescents, the importance of clinical monitoring

Multiple endocrine neoplasia type 1 in children and adolescents, the importance of clinical monitoring

A Novel CDKN1B mutation in multiple endocrine neoplasia type 4

A Novel CDKN1B mutation in multiple endocrine neoplasia type 4

Distinctive features of primary hyperparathyroidism in multiple endocrine neoplasia type 2a: a series of five cases

Distinctive features of primary hyperparathyroidism in multiple endocrine neoplasia type 2a: a series of five cases

Adrenal phenotype in multiple endocrine neoplasia type 1

Adrenal phenotype in multiple endocrine neoplasia type 1

Role of MEN1 mutation on postoperative outcomes in patients with Multiple Endocrine Neoplasia type 1-related primary hyperparathyroidism: a single center experience

Role of MEN1 mutation on postoperative outcomes in patients with Multiple Endocrine Neoplasia type 1-related primary hyperparathyroidism: a single center experience

A case study of multiple endocrine neoplasia type 2a

A case study of multiple endocrine neoplasia type 2a

Car accident leading to an incidental finding of multiple endocrine neoplasia type 1 (MEN-1)

Car accident leading to an incidental finding of multiple endocrine neoplasia type 1 (MEN-1)