scholarly journals Molecular Alterations in Sporadic Primary Hyperparathyroidism

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Maria Inês Alvelos ◽  
Maria Mendes ◽  
Paula Soares
Keyword(s):  
Primary Hyperparathyroidism ◽  
Molecular Mechanisms ◽  
Benign Lesion ◽  
Protein Overexpression ◽  
Endocrine Disorder ◽  
Molecular Alterations ◽  
Familial Form ◽  
Somatic Alterations ◽  
Sporadic Primary Hyperparathyroidism ◽  
Parathyroid Tumours

Primary hyperparathyroidism (PHPT) is a frequent endocrine disorder characterized by an excessive autonomous production and release of parathyroid hormone (PTH) by the parathyroid glands. This endocrinopathy may result from the development of a benign lesion (adenoma or hyperplasia) or from a carcinoma. Most of the PHPT cases occur sporadically; however, approximately 10% of the patients present a familial form of the disease. The molecular mechanisms underlying the pathogenesis of sporadic PHPT are incompletely understood, even though somatic alterations in MEN1 gene and CCND1 protein overexpression are frequently observed. The MEN1 gene is mutated in about 30% of the parathyroid tumours and the protooncogene CCND1 is implicated in parathyroid neoplasia by rearrangements, leading to an overexpression of CCND1 protein in parathyroid cells. The aim of this work is to briefly update the molecular alterations underlying sporadic primary hyperparathyroidism.

scholarly journals Different somatic alterations of the HRPT2 gene in a patient with recurrent sporadic primary hyperparathyroidism carrying an HRPT2 germline mutation

2007 ◽  
Vol 14 (2) ◽  
pp. 493-499 ◽  
Author(s):  
F Cetani ◽  
E Pardi ◽  
E Ambrogini ◽  
P Viacava ◽  
S Borsari ◽  
...  
Keyword(s):  
Primary Hyperparathyroidism ◽  
Germline Mutation ◽  
Parathyroid Tissue ◽  
Parathyroid Tumors ◽  
Familial Form ◽  
Somatic Alterations ◽  
Sporadic Primary Hyperparathyroidism ◽  
Hrpt2 Gene ◽  
Genetic Events

Early onset of primary hyperparathyroidism (PHPT) and multiglandular involvement suggest a familial form in which germline mutation of a PHPT-related gene(s) and a somatic event at the same locus can be often demonstrated. We investigated the involvement of multiple endocrine neoplasia type 1 (MEN1) and HRPT2 genes in a 39-year-old man with recurrent PHPT. PHPT was firstly diagnosed at the age of 21 and the patient had two recurrences separated by extended periods of normocalcemia. This unusual history prompted us to investigate other family members and study the MEN1 and HRPT2 genes. An HRPT2 germline missense mutation in exon 3 (R91P) was found in the index case, which was associated with different HRPT2 somatic alterations in each of the three examined parathyroid tumors. These findings are consistent with Knudson’s ‘two hit’ concept of biallelic inactivation of classical tumor suppressor genes. Screening of 15 asymptomatic relatives was negative for the R91P germline mutation. All the three abnormal parathyroid specimens showed cystic features at histology and were negative for parafibromin immunostaining. In one specimen, diffuse parafibromin staining was evident in a rim of normal parathyroid tissue surrounding the adenomatous lesion. Our study shows that different somatic genetic events at the HRPT2 locus are responsible for the asynchronous occurrence of multiple adenomas in a patient carrying an HRPT2 germline mutation. The finding of diffuse parafibromin staining in a rim of normal parathyroid tissue, but not in the contiguous adenomatous lesion, reinforces the concept that loss of parafibromin expression is responsible for the development of parathyroid tumors in this setting.

scholarly journals Evaluation of malignant parathyroid tumours in two European cohorts of patients with sporadic primary hyperparathyroidism

2015 ◽  
Vol 401 (7) ◽  
pp. 943-951 ◽  
Author(s):  
Arturs Ozolins ◽  
Zenons Narbuts ◽  
Andrejs Vanags ◽  
Zane Simtniece ◽  
Zane Visnevska ◽  
...  
Keyword(s):  
Primary Hyperparathyroidism ◽  
Sporadic Primary Hyperparathyroidism ◽  
Parathyroid Tumours

scholarly journals Clinicopathological correlates of hyperparathyroidism

2015 ◽  
Vol 68 (10) ◽  
pp. 771-787 ◽  
Author(s):  
Kai Duan ◽  
Karen Gomez Hernandez ◽  
Ozgur Mete
Keyword(s):  
Primary Hyperparathyroidism ◽  
Molecular Mechanisms ◽  
Parathyroid Tissue ◽  
Parathyroid Hyperplasia ◽  
Tumour Suppressor Genes ◽  
Tertiary Hyperparathyroidism ◽  
Intraoperative Pth ◽  
Prevalent Disease ◽  
Parathyroid Tumours ◽  
Men 2A

Hyperparathyroidism is a common endocrine disorder with potential complications on the skeletal, renal, neurocognitive and cardiovascular systems. While most cases (95%) occur sporadically, about 5% are associated with a hereditary syndrome: multiple endocrine neoplasia syndromes (MEN-1, MEN-2A, MEN-4), hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH-1, FHH-2, FHH-3), familial hypercalciuric hypercalcaemia, neonatal severe hyperparathyroidism and isolated familial hyperparathyroidism. Recently, molecular mechanisms underlying possible tumour suppressor genes (MEN1, CDC73/HRPT2, CDKIs, APC, SFRPs, GSK3β, RASSF1A, HIC1, RIZ1, WT1, CaSR, GNA11, AP2S1) and proto-oncogenes (CCND1/PRAD1, RET, ZFX, CTNNB1, EZH2) have been uncovered in the pathogenesis of hyperparathyroidism. While bi-allelic inactivation of CDC73/HRPT2 seems unique to parathyroid malignancy, aberrant activation of cyclin D1 and Wnt/β-catenin signalling has been reported in benign and malignant parathyroid tumours. Clinicopathological correlates of primary hyperparathyroidism include parathyroid adenoma (80–85%), hyperplasia (10–15%) and carcinoma (<1–5%). Secondary hyperparathyroidism generally presents with diffuse parathyroid hyperplasia, whereas tertiary hyperparathyroidism reflects the emergence of autonomous parathyroid hormone (PTH)-producing neoplasm(s) from secondary parathyroid hyperplasia. Surgical resection of abnormal parathyroid tissue remains the only curative treatment in primary hyperparathyroidism, and parathyroidectomy specimens are frequently encountered in this setting. Clinical and biochemical features, including intraoperative PTH levels, number, weight and size of the affected parathyroid gland(s), are crucial parameters to consider when rendering an accurate diagnosis of parathyroid proliferations. This review provides an update on the expanding knowledge of hyperparathyroidism and highlights the clinicopathological correlations of this prevalent disease.

scholarly journals Wedding of Molecular Alterations and Immune Checkpoint Blockade: Genomics as a Matchmaker

2021 ◽  
Author(s):  
Elena Fountzilas ◽  
Razelle Kurzrock ◽  
Henry Hiep Vo ◽  
Apostolia-Maria Tsimberidou
Keyword(s):  
Molecular Mechanisms ◽  
Cell Receptor ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Beta Catenin ◽  
Molecular Alterations ◽  
Receptor Repertoire ◽  
Repair Deficiency ◽  
Tumor Mutational Burden

Abstract The development of checkpoint blockade immunotherapy has transformed the medical oncology armamentarium. But, despite its favorable impact on clinical outcomes, immunotherapy benefits only a subset of patients, and a substantial proportion of these individuals eventually manifest resistance. Serious immune-related adverse events and hyper-progression have also been reported. It is therefore essential to understand the molecular mechanisms and identify the drivers of therapeutic response and resistance. In this review, we provide an overview of the current and emerging clinically relevant genomic biomarkers implicated in checkpoint blockade outcome. U.S. Food and Drug Administration–approved molecular biomarkers of immunotherapy response include mismatch repair deficiency/microsatellite instability and tumor mutational burden ≥10 mutations/megabase. Investigational genomic-associated biomarkers for immunotherapy response include alterations of the following genes/associated pathways: chromatin remodeling (ARID1A, PBRM1, SMARCA4, SMARCB1, BAP1), major histocompatibility complex, specific (e.g., ultraviolet, APOBEC) mutational signatures, T-cell receptor repertoire, PDL1, POLE/POLD1, and neo-antigens produced by the mutanome; those potentially associated with resistance include β2-microglobulin, EGFR, Keap1, JAK1/JAK2/interferon-gamma signaling, MDM2, PTEN, STK11, and Wnt/Beta-catenin pathway alterations. Prospective clinical trials are needed to assess the role of a composite of these biomarkers in order to optimize the implementation of precision immunotherapy in patient care.

scholarly journals Molecular Alterations in Sporadic and SOD1-ALS Immortalized Lymphocytes: Towards a Personalized Therapy

2021 ◽  
Vol 22 (6) ◽  
pp. 3007
Author(s):  
Isabel Lastres-Becker ◽  
Gracia Porras ◽  
Marina Arribas-Blázquez ◽  
Inés Maestro ◽  
Daniel Borrego-Hernández ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Autophagic Flux ◽  
Metabolic Disturbances ◽  
Molecular Alterations ◽  
Healthy Donors ◽  
Inflammatory Profile ◽  
Als Patients

Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition where motor neurons (MNs) degenerate. Most of the ALS cases are sporadic (sALS), whereas 10% are hereditarily transmitted (fALS), among which mutations are found in the gene that codes for the enzyme superoxide dismutase 1 (SOD1). A central question in ALS field is whether causative mutations display selective alterations not found in sALS patients, or they converge on shared molecular pathways. To identify specific and common mechanisms for designing appropriate therapeutic interventions, we focused on the SOD1-mutated (SOD1-ALS) versus sALS patients. Since ALS pathology involves different cell types other than MNs, we generated lymphoblastoid cell lines (LCLs) from sALS and SOD1-ALS patients and healthy donors and investigated whether they show changes in oxidative stress, mitochondrial dysfunction, metabolic disturbances, the antioxidant NRF2 pathway, inflammatory profile, and autophagic flux. Both oxidative phosphorylation and glycolysis appear to be upregulated in lymphoblasts from sALS and SOD1-ALS. Our results indicate significant differences in NRF2/ARE pathway between sALS and SOD1-ALS lymphoblasts. Furthermore, levels of inflammatory cytokines and autophagic flux discriminate between sALS and SOD1-ALS lymphoblasts. Overall, different molecular mechanisms are involved in sALS and SOD1-ALS patients and thus, personalized medicine should be developed for each case.

Chief cell and clear cell parathyroid adenoma do not influence clinical and biochemical expression of the sporadic primary hyperparathyroidism

Endocrine ◽  
2012 ◽  
Vol 43 (2) ◽  
pp. 440-443 ◽  
Author(s):  
Shweta Varshney ◽  
Sanjay Kumar Bhadada ◽  
Uma Nahar ◽  
Viral N. Shah ◽  
Anil Bhansali ◽  
...  
Keyword(s):  
Primary Hyperparathyroidism ◽  
Parathyroid Adenoma ◽  
Clear Cell ◽  
Chief Cell ◽  
Sporadic Primary Hyperparathyroidism

scholarly journals SAT-058 A Rare Case of Primary Hyperparathyroidism in a Pediatric Patient

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Natalia Salazar ◽  
Jeff M Merz ◽  
Liliana Burdea ◽  
Carla Minutti
Keyword(s):  
Abdominal Pain ◽  
Primary Hyperparathyroidism ◽  
Clinical Significance ◽  
Parathyroid Tissue ◽  
High Serum ◽  
Genetic Evaluation ◽  
Atypical Presentation ◽  
Pediatric Endocrinology ◽  
Endocrine Disorder ◽  
Ret Gene

Abstract Introduction: Primary hyperparathyroidism (PHPT) is the third most common endocrine disorder in adult patients, but it is rare in pediatric patients. It is usually diagnosed when patients present with symptomatic hypercalcemia or known complications. In children, atypical presentation often results in delayed diagnosis and increased morbidity. We report a 10-year-old boy presenting with abdominal pain and emesis, found to have hypercalcemia and, ultimately, PHPT. His genetic evaluation was notable for a mutation in the RET gene (3.2C&gt;A) of unknown clinical significance. Case presentation: A 10-year-old male with a history of constipation presented to the emergency department with five days of abdominal pain and emesis. Initial workup revealed high serum calcium (Ca) of 17.3 mg/dL (8.7-10.7) and ionized Ca (ICal) of 2.01 mmol/L (0.95-1.32). Further evaluations revealed low phosphorus level 3.5 mg/dL (4.5-6.5) and high parathyroid hormone level (iPTH) of 329.2 pg/mL (8.0-85.0). These findings were consistent with PHPT. Neck US demonstrated a cervical mass in the mid-right thyroid measuring 0.5 x0.3 x0.5cm, questionable for parathyroid adenoma, which was confirmed with 99mTc-MIBI scintigraphy and neck CT. His Ca level initially responded to fluid resuscitation and Lasix, with Ca level decreasing to 13.6. However, on hospital day two, his Ca level became refractory to all interventions, rising to 16 and prompting the use of bisphosphonates. The patient underwent neck exploration with partial parathyroidectomy and lymph node excision. Pathology revealed hypercellular parathyroid tissue consistent with parathyroid hyperplasia. Intraoperatively iPTH was reduced from 3,134.7 to 79.8 and remained within normal limits since. Postoperatively course was uncomplicated, and the patient was discharged home on oral Ca carbonate and vitamin D. A genetic evaluation was remarkable for a change in the RET gene (3.2C&gt;A), a finding of unknown clinical significance. This change has not been seen in association with an individual who fulfills the clinical diagnosis of MEN2A. To further determine if the variant identified in the RET gene is a benign variant, the mother was tested for MEN2A and was negative. Father could not be tested, but family history was significant for thyroid malignancies. The patient is currently doing well four months postoperatively. His Ca level remains normal. Due to the genetic finding and the concern of MEN2A syndrome, the patient is followed closely by pediatric endocrinology and genetics. Conclusion: PHPT is a common endocrine disorder in adults but rare in children. The diagnosis of pediatric PHPT is almost always delayed due to atypical presentation and rarity of the disease. As secondary organ damage is common, a multi-organ assessment is mandatory. Due to the association with other syndromes, a genetic evaluation should be performed.

Sign in / Sign up

Export Citation Format

Share Document