Search Results (36)

Multiple endocrine neoplasia (MEN) syndromes are rare hereditary disorders characterized by the development of multiple endocrine and non-endocrine tumours with variable penetrance and age-dependent expression. Although uncommon, these syndromes are highly relevant from both biological and clinical perspectives, as they exemplify the direct link between germline genetic alterations and tumorigenesis. Early tumour detection is critical in MEN syndromes because many associated neoplasms—such as medullary thyroid carcinoma (MTC), pancreatic neuroendocrine tumours (NETs), pheochromocytomas, and parathyroid disease—may remain clinically silent for prolonged periods while retaining malignant potential. Delayed diagnosis is associated with advanced disease and worse outcomes, whereas early identification enables curative or organ-preserving interventions. This clinical challenge has driven the development of integrated diagnostic strategies combining genetic testing, biochemical markers, and imaging. Among these, genetic testing plays a pivotal role, providing definitive diagnosis, enabling family screening, and guiding risk-adapted surveillance. The aim of this review is to provide a comprehensive synthesis of genetically driven diagnostics in MEN syndromes, outlining the current state of the art and future directions in precision medicine. Full article

Background/Objectives: The RET (Rearranged during Transfection) gene encodes a receptor tyrosine kinase. RET plays a critical role in embryonic development and postnatal physiology. This review provides a comprehensive overview of RET-associated disorders, focusing on the molecular mechanisms of RET activation, associated clinical phenotypes and therapeutic implications. In addition, we present an updated RET mutation database. Methods: RET mutation database is built through the integration and curation of data from two major RET mutation repositories: the Leiden Open Variation Database (LOVD) and the Cancer Knowledge Base (CKB) as well as information derived from the ClinVar database. Results: To date, 78 pathogenic RET mutations have been identified, among these, 71 (91.0%) are single nucleotide substitutions (missense variants), 2 (2.6%) are deletions, 1 (1.3%) are indels, 2 (2.6%) are nonsense mutations and 1 (1.3%) mutation affecting the introns. A pronounced clustering was observed in exons 10–11, accounting for ~60% of cases, suggesting a potential mutational hotspot with structural or functional relevance. Conclusions: Aberrant RET activation, resulting from activating missense variants, gene fusions, or overexpression, underlies a wide spectrum of human diseases. These include multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid carcinoma (MTC), Hirschsprung disease, and pheochromocytoma. The existence and use of a database classifying variants in the RET gene plays a fundamental role in molecular diagnostics and personalized medicine. Full article

Early detection of cancer remains a key challenge because current SPR-PCF sensors lack both sensitivity and robust light–analyte interaction. To overcome these limitations, this study proposed and validated an SPR biosensor utilizing MXene-functionalized PCF. By introducing a composite structure of MXene nanomaterials and Au, the detection performance of the sensor was significantly improved. The sensor adopts a circular air hole arrangement and double-groove morphology design and leverages MXene’s high conductivity and gold’s chemical stability to simultaneously enhance plasmonic coupling and biocompatibility. Through FEM-based structural optimization of the air hole diameter, Au layer thickness, and groove shape, the sensor exhibited outstanding refractive-index detection performance with a wavelength sensitivity of 11,072 nm/RIU, an impressive quality factor reaching 201.3 RIU⁻¹, and a resolution as fine as 9.03 × 10⁻⁶ RIU. The simulation results demonstrated the capability of the sensor to discriminate six distinct cancer-cell types (cervical cancer HeLa, leukemia Jurkat, pheochromocytoma PC-12, triple-negative breast cancer MDA-MB-231, and breast cancer MCF-7) with high sensitivity and verify its ability to detect pan-cancer species. This study demonstrates an innovative approach for constructing a high-performance SPR sensing platform that has important application potential in the context of the early detection of multiple cancers. Full article

Researchers have long focused on the accumulation of amyloid beta (Aβ) peptides in the brain as a primary pathological hallmark driving cognitive decline. This study investigated the neuroprotective effects of Rosa rugosa (RR) root extract and its key bioactive constituent, oleamide, against amyloid beta (Aβ)-induced neurotoxicity. Initially, an ethanolic extract of RR root was screened via in vitro assays to assess antioxidant and cytoprotective potential in rat pheochromocytoma cells. Subsequent fractionation, open-column chromatography, and preparatory thin-layer chromatography led to the isolation of oleamide, confirmed by gas chromatography–mass spectrometry and ¹H/¹³C nuclear magnetic resonance analyses. In vivo experiments using intracerebroventricularly injected Aβ in male mice demonstrated that both RR root extract and oleamide significantly improved cognitive performance in the Y-maze and passive avoidance tests. Additionally, oleamide restored acetylcholine levels and reduced malondialdehyde concentrations in brain tissue, indicating mitigation of oxidative stress and support of cholinergic function. No significant toxicity was observed, as evidenced by stable serum transaminase levels and unaltered body or brain weights. These findings highlight oleamide’s potential to protect against Aβ-driven pathology through multiple mechanisms, including reduced lipid peroxidation and improved neurotransmission. Further investigations into oleamide’s molecular targets and synergy with existing therapies may advance its development as a novel candidate for Alzheimer’s disease prevention or adjunct treatment. Full article

Background: Primary hyperparathyroidism (PHPT) represents a multi-faced disease with a wide spectrum of manifestations. Familial forms of PHPT (affecting up to 10% of the cases) involve a particular category that encompasses a large range of hereditary syndromes, including parathyroid hyper-function, frequently in the setting of a multi-glandular disease. Objective: The aim was to analyze the most recent findings regarding PHPT in multiple endocrine neoplasia type 2 (MEN2) to a better understanding of the timing with respect to the associated ailments, MEN2-related PHPT (MEN2-PHPT) clinical and genetic particularities, optimum diagnostic, and overall management, particularly, surgical outcomes. Methods: This was a PubMed-based compressive review with regard to the latest data published in English from January 2020 until January 2025, using the following keywords: “primary hyperparathyroidism” and “multiple endocrine neoplasia”, “multiple endocrine neoplasia type 2”, “MEN2”, or “MEN2A”. We included original full-length studies of any study design that provided clinically relevant data in MEN2-PHPT and excluded reviews, meta-analysis, and case reports/series. Results: A total of 3783 individuals confirmed with MEN2 or RET pathogenic variants carriers were analyzed across 14 studies that provided data on PHPT. The prevalence of MEN2-PHPT subjects varied between 7.84% and 31.3%, with particularly low rates in non-index patients (3.8%). PHPT was the first syndrome manifestation in 0.9% of MEN2 patients. In terms of gender distribution, females represented 42.85% or 54.9% (similar rates between women and men, and only a single cohort showed a female rate up to 80%). Most subjects were diagnosed with PHPT and underwent surgery in the third or fourth decade of life. The highest median age at MEN2 diagnosis was 42 years. The youngest patients were RET pathogenic variants carriers who underwent (genetic) screening with median ages of 12 or 14 years. RET pathogenic variants analysis (n = 10/14 studies) showed that 16.67% of patients with p.Cys634Arg and 37.5% of those with p.Cys611Tyr had symptomatic PHPT, while those with p.Cys618Phe and p.Leu790Phe were asymptomatic. Timing analysis with respect to the medullary thyroid carcinoma diagnosis showed synchronous PHPT diagnosis in 80% and metachronous in 10% of MEN2 patients; with respect to MEN2-pheochromocytoma, synchronous diagnosis of PHPT was found in 56%, while pheochromocytoma was identified before PHPT in 22% of the cases and after PHPT in 22%. Studies (n = 10/14, N = 156 subjects with MEN2-PHPT) on parathyroidectomy identified that 72.7% to 100% of the individuals underwent surgery, typically performed in adulthood, at ages spanning from a mean of 34.7 to 48.5 years. The post-surgery outcomes varied (e.g., the rate for persistent PHPT was of 0%, 8% to 16.7%; recurrent PHPT of 12.5% to 23%; permanent hypoparathyroidism of 33% to 46%; permanent unilateral vocal cord palsy of 0% up to16.7%). Data regarding the number of involved glands (n = 7, N = 77): the prevalence of multi-glandular disease was pinpointed between 12.5% and 50%. Conclusions: MEN2-PHPT involved unexpected high rates of single-gland involvement (from 33.3% to 87.5%), probably due to an early detection across genetic screening. Traditional female higher prevalence in PHPT was not confirmed in most MEN2 cohorts. As expected, a younger age at PHPT diagnosis and surgery than seen in non-MEN2 patients was identified, being tidily connected with the syndromic constellation of tumors/malignancies. Overall, approximately, one out of ten patients were further confirmed with MEN2 starting with PHPT as the first clinically manifested element. Full article

Background: Multiple endocrine neoplasia type 2A (MEN 2A) is a rare hereditary cancer syndrome caused by pathogenic variants in the rearranged during transfection (RET) gene and is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), primary hyperparathyroidism (PHPT), cutaneous lichen amyloidosis (CLA), and Hirschsprung’s disease. Phenotypic data on the RET C611Y variant remain sparse. Consequently, we aimed to establish a clinical risk profile. Methods: We conducted a nationwide study of all cases (n = 128) born after 1 January 1930 and recognized as carrying the RET C611Y variant in Denmark before 1 April 2021. Results: The median follow-up after birth was 47 years (range, 3–92). Age-related penetrance at age 70 years for MTC was 98% (CI, 91–100), for PHEO 24% (CI, 16–37), and for PHPT 10% (CI, 5–20). None had CLA or Hirschsprung’s disease. The age-related progression of MTC was significant (p < 0.001). The mean age at T0N0M0 was 16 years (CI, 12–20), at T1-4N0M0 38 years (CI, 34–42), at TxN1M0 45 years (CI, 38–53) and at TxNxM1 49 years (CI, 36–61). At the last follow-up, 56% of thyroidectomized cases (n = 103) were biochemically cured. Overall survival at 70 years was 74% (CI, 59–84). Conclusions: RET C611Y is associated with a very high penetrance of MTC and a low penetrance of PHEO and PHPT. CLA and Hirschsprung’s disease almost never occur. MTC seems moderately aggressive, but large variability can be seen. Overall survival may be comparable to that of the general population. Full article

Neurofibromatosis is a genetic disorder arising de novo or with an autosomal dominant transmission that typically presents either at birth or in early childhood, manifesting through distinctive clinical features such as multiple café-au-lait spots, benign tumors in the skin, bone enlargement, and deformities. This literature review aims to resume the spectrum of maternal and fetal complications encountered in pregnant women with neurofibromatosis type 1 (NF1). Thorough research was conducted on databases such as Web of Science, PubMed, Science Direct, Google Scholar, and Wiley Online Library. This review includes 48 case reports, original studies, and reviews on NF1 in pregnancy. The research on the interlink between NF1 and fertility and its influence on human-assisted reproduction techniques is limited. Preimplantation testing (by in vitro fertilization) and prenatal diagnosis (by chorionic villus sampling or amniocentesis) are available to detect affected fetuses. However, genotype–phenotype correlation is difficult to predict. Preconceptional planning and targeted investigations are crucial in understanding the extent of maternal disease. Although in some cases lesions can evolve rapidly during pregnancy, most pregnancies and births in NF1 go well with careful planning. There is a higher incidence of pheochromocytomas and pre-eclampsia, vascular rupture, and cardio-respiratory issues. Anesthesia at birth is a challenge in most cases, and before offering spinal anesthesia, imaging tests should be performed to characterize spinal lesions. General anesthesia may also be challenging when the disease affects the face, neck, upper spine, or airways. Birth-related difficulties may arise because of large neurofibromas located at the level of skin incision or birth canal; uterine atony may be expected if there are uterine lesions. Some complications can develop in postpartum, and affected women should be carefully followed even after pregnancy. Fetal risks include preterm birth (spontaneous or iatrogenic), growth restriction and developmental issues, birth complications, cardiovascular risk, and fetal/neonatal demise. Pregnancies in women with NF1 should be regarded as high-risk and followed in a multidisciplinary fashion. Careful assessment of lesions is of utmost importance before and during pregnancy for anticipating potential maternal risks and before birth to plan anesthesia and delivery. Full article

Background: Quantifying urinary catecholamines and metanephrines is essential for the clinical screening and diagnosis of neuroendocrine tumours. HPLC with electrochemical detection (HPLC-ECD) is commonly used for this type of analysis but requires extensive sample cleanup. Simple and rapid dilute-and-shoot LC–multiple-reaction monitoring (MRM)-MS assays have been developed for quantitating these analytes in urine but have not yet been validated according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Methods: A simple dilute-and-shoot sample preparation without derivatization was used. C18 RP-UPLC-MRM-MS and positive-ion ESI were used, usually with two transitions per analyte being monitored. Certified deuterated internal standards were used for each analyte. Results: This assay was validated according to the CLSI C62-A guidelines, including accuracy/trueness, imprecision, sensitivity, specificity, carryover, stability, and linearity. The final MRM-MS method was compared to the established HPLC-ECD clinical chemistry reference method. The run time was reduced from 25 min to 5 min. Conclusions: A simple, robust, rapid, and cost-effective LC-MRM-MS assay for measuring urinary catecholamines and metanephrines was developed and validated according to the CLSI guidelines. This validated method requires minimal sample manipulation before analysis and provides sensitivity, specificity, and improved precision. The implementation of this assay in clinical laboratories will facilitate early and accurate diagnosis. Full article

Head and neck paragangliomas (HNPGLs) are rare neoplasms that, along with pheochromocytomas and extra-adrenal paragangliomas, are associated with inherited mutations in at least 12 susceptibility genes in approximately 40% of cases. However, due to the rarity of HNPGLs, only a series of small-scale studies and individual cases have reported mutations in additional genes that may be involved in tumorigenesis. Consequently, numerous disease-causing mutations and genes responsible for the pathogenesis of HNPGLs remain poorly investigated. The aim of this study was to gain a deeper understanding of the genetic basis of HNPGLs by focusing on variants in genes that were not previously identified as well-known drivers. A whole-exome data analysis was conducted on a representative set of 152 HNPGLs. In 30% of the tumors examined, 53 potentially deleterious variants were identified in 36 different genes. The analysis identified pathogenic or likely pathogenic variants in the ARNT, IDH2, L2HGDH, MYH3, PIK3CA, and TERT genes. A functional network analysis of the mutated genes revealed numerous associations and a list of metabolic pathways (e.g., the TCA cycle, carbon metabolism, pyruvate metabolism, etc.) and signaling pathways (e.g., HIF1, PI3K-Akt, FoxO, AMPK, MAPK, etc.) that may play an important role in the development of HNPGLs. The identified range of genetic alterations affecting multiple genes and, potentially, influencing diverse cellular pathways provides an enhanced molecular genetic characterization of HNPGLs. Full article

Background: Medullary thyroid carcinoma (MTC), the third most frequent histological type of thyroid malignancy, may be found isolated or as part of multiple endocrine neoplasia type 2 (MEN2). One particular subtype of this autosomal dominant-transmitted syndrome includes an association with cutaneous lichen amyloidosis, although, generally, a tide genotype–phenotype correlation is described in patients who carry RET proto-oncogene pathogenic variants. Methods: Our objective was to provide an endocrine perspective of a case series diagnosed with RET-positive familial MTC associated with cutaneous primary lichen amyloidosis amid the confirmation of MEN2. Six members of the same family had cutaneous lesion with different features (from hyperpigmented, velvety to red/pink appearance) and four of them harbored a RET pathogenic variant at 634 codon (exon 11): c.1900T>G, p.634G (TGC634CGC). Results: All six patients were females with the lesion at the interscapular region. Except for two women, four of these subjects were investigated and had MTC (three of them with postoperatory confirmation). The youngest affected individual was 6 years old. The three adult females were confirmed with RET pathogenic variant during their 30s, while the girl underwent the familial screening as a newborn. None of them had primary hyperparathyroidism until the present time, except for one subject, and two out of the three adults also had bilateral pheochromocytoma. Notably, all patients were rather asymptomatic from the endocrine perspective at the moment when endocrine tumor/cancer was confirmed, and the skin was progressively affected a few years before the actual MEN2 confirmation. Conclusions: This case series highlights the following key message: awareness of the dermatologic findings in MTC/MEN2 patients is essential since lesions such as cutaneous lichen amyloidosis might represent the skin signature of the endocrine condition even before the actual endocrine manifestations. These data add to the limited published reports with respect to this particular presentation, noting the fact that RET-C634 is the most frequent pathogenic variant in MEN2-associated lichen amyloidosis; females are more often affected; the interscapular region is the preferred site; the age of diagnosis might be within the third decade of life, while we reported one of the youngest patients with the lesion. The same RET pathogenic variant is not associated with the same dermatologic features as shown in the vignette. The same RET mutation does not mean that all family members will present the same skin anomaly. Full article

Pheochromocytoma and paraganglioma (PPGL) are rare tumors derived from the adrenal medulla and extra-adrenal chromaffin cells. Diagnosis is often challenging due to the great variability in clinical presentation; the complexity of management due to the dangerous effects of catecholamine excess and the potentially malignant behavior require in-depth knowledge of the pathology and multidisciplinary management. Nowadays, diagnostic ability has certainly improved and guidelines and consensus documents for treatment and follow-up are available. A major impulse to the development of this knowledge has come from the new findings on the genetic and molecular characteristics of PPGLs. Germline mutation in susceptibility genes is detected in 40% of subjects, with a mutation frequency of 10–12% also in patients with sporadic presentation and genetic testing should be incorporated within clinical care. PPGL susceptibility genes include “old genes” associated with Neurofibromatosis type 1 (NF1 gene), Von Hippel Lindau syndrome (VHL gene) and Multiple Endocrine Neoplasia type 2 syndrome (RET gene), the family of SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), and genes less frequently involved such as TMEM, MAX, and FH. Each gene has a different risk of relapse, malignancy, and other organ involvement; for mutation carriers, affected or asymptomatic, it is possible to define a tailored long-life surveillance program according to the gene involved. In addition, molecular characterization of the tumor has allowed the identification of somatic mutations in other driver genes, bringing to 70% the PPGLs for which we know the mechanisms of tumorigenesis. This has expanded the catalog of tumor driver genes, which are identifiable in up to 70% of patients Integrated genomic and transcriptomic data over the last 10 years have revealed three distinct major molecular signatures, triggered by pathogenic variants in susceptibility genes and characterized by the activation of a specific oncogenic signaling: the pseudo hypoxic, the kinase, and the Wnt signaling pathways. These molecular clusters show a different biochemical phenotype and clinical behavior; they may also represent the prerequisite for implementing customized therapy and follow-up. Full article

Myocardial remodeling is developed by increased stress in acute or chronic pathophysiologies. Stressed heart morphology (SHM) is a new description representing basal septal hypertrophy (BSH) caused by emotional stress and chronic stress due to increased afterload in hypertension. Acute stress cardiomyopathy (ASC) and hypertension could be together in clinical practice. Therefore, there are some geometric and functional aspects regarding this specific location, septal base under acute and chronic stress stimuli. The findings by our and the other research groups support that hypertension-mediated myocardial involvement could be pre-existed in ASC cases. Beyond a frequently seen predominant base, hyperkinetic tissue response is detected in both hypertension and ASC. Furthermore, hypertension is the responsible factor in recurrent ASC. The most supportive prospective finding is BSH in which a hypercontractile base takes a longer time to exist morphologically than an acutely developed syndrome under both physiologic exercise and pressure overload by transaortic binding in small animals using microimaging. However, cardiac decompensation with apical ballooning could mask the possible underlying hypertensive disease. In fact, enough time for the assessment of previous hypertension history or segmental analysis could not be provided in an emergency unit, since ASC is accepted as an acute coronary syndrome during an acute episode. Additional supportive findings for SHM are increased stress scores in hypertensive BSH and the existence of similar tissue aspects in excessive sympathetic overdrive like pheochromocytoma which could result in both hypertensive disease and ASC. Exercise hypertension as the typical form of blood pressure variability is the sum of physiologic exercise and pathologic increased blood pressure and results in increased mortality. Hypertension is not rare in patients with a high stress score and leads to repetitive attacks in ASC supporting the important role of an emotional component as well as the potential danger due to multiple stressors at the same time. In the current review, the impact of multiple stressors on segmental or global myocardial remodeling and the hazardous potential of multiple stressors at the same time are discussed. As a result, incidentally determined segmental remodeling could be recalled in patients with multiple stressors and contribute to the early and combined management of both hypertension and chronic stress in the prevention of global remodeling and heart failure. Full article

Background and Objectives: Paragangliomas (PGLs) are rare neuroendocrine extra-adrenal tumors that could be secreting mass. The symptoms are the typical triad of paroxysmal headache, hypertension and sweating, but could also be accompanied by symptoms involving multiple organs. Surgery is the gold standard treatment for both PGLs and pheochromocytomas (PHEOs). Material and Methods: We used a computerized endocrine surgery registry to record the demographic and clinical data of 153 patients who underwent surgery for PPGL between 2010 and 2023 at our hospital. Results: Thirteen patients (8.43%) with paragangliomas underwent surgery at our institute. Five patients presented symptomatic syndrome. Preoperative investigations included enhanced abdominal CT (nine patients) and enhanced MRI (seven patients). In cases of suspicious mass, we performed 131I-MIBG scans (two patients) or 68GA-DOTATOC PET-CT scans (11 patients). Laparoscopic approach was used in four cases (30.7%) and abdominal laparotomy in the other nine (69.3%). Biochemical tests were performed on all patients. Conclusions: In this retrospective study, we discuss the multidisciplinary management in our institute of this rare disease, from its challenging diagnosis to the surgical strategy for PGLs. Laparoscopic surgery is the gold standard, but a tailored approach should be adopted for each patient. Full article

Lysophosphatidic acid (LPA) is a lipid mediator that binds to G-protein-coupled receptors, eliciting a wide variety of responses in mammalian cells. Lyso-phospholipids generated via phospholipase A₂ (PLA₂) can be converted to LPA by a lysophospholipase D (lyso-PLD). Secreted lyso-PLDs have been studied in more detail than membrane-localized lyso-PLDs. This study utilized in vitro enzyme assays with fluorescent substrates to examine LPA generation in membranes from multiple mammalian cell lines (PC12, rat pheochromocytoma; A7r5, rat vascular smooth muscle; Rat-1, rat fibroblast; PC-3, human prostate carcinoma; and SKOV-3 and OVCAR-3, human ovarian carcinoma). The results show that membranes contain a lyso-PLD activity that generates LPA from a fluorescent alkyl-lyso-phosphatidylcholine, as well as from naturally occurring acyl-linked lysophospholipids. Membrane lyso-PLD and PLD activities were distinguished by multiple criteria, including lack of effect of PLD2 over-expression on lyso-PLD activity and differential sensitivities to vanadate (PLD inhibitor) and iodate (lyso-PLD inhibitor). Based on several lines of evidence, including siRNA knockdown, membrane lyso-PLD is distinct from autotaxin, a secreted lyso-PLD. PC-3 cells express GDE4 and GDE7, recently described lyso-PLDs that localize to membranes. These findings demonstrate that membrane-associated lyso-D activity, expressed by multiple mammalian cell lines, can contribute to LPA production. Full article

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. Full article