Primary hyperparathyroidism: Disease of diverse genetic, symptomatic, and biochemical phenotypes

Medina, Jesús E.; Randolph, Gregory W.; Angelos, Peter; Zafereo, Mark; Tufano, Ralph P.; Kowalski, Luiz Paulo; Montenegro, Fábio Luiz de Menezes; Owen, Randall P.; Khafif, Avi; Suárez, Carlos; Shaha, Ashok R.; Rodrigo, Juan P.; Krempl, Greg A.; Rinaldo, Alessandra; Silver, Carl E.; Ferlito, Alfio

doi:10.1002/hed.26861

Cited by 7 publications

(8 citation statements)

References 116 publications

(144 reference statements)

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“…This is supported by molecular studies evaluating parathyroid disease in multiple endocrine neoplasia type 1 (MEN1) and multiple endocrine neoplasia type 4 (MEN4) cohorts and tertiary HPTH, traditionally associated with multiglandular hyperplasia, which demonstrated clonal proliferations in the background of polyglandular hyperplasia 16–19,21–23. It has been reported that up to 25% of parathyroid hyperplasia are a manifestation of a familial syndrome 16–20,22. As a result, the current WHO 2022 classification recommends the use of the term PHPT-related multiglandular parathyroid disease which more accurately reflects the underlying molecular pathogenesis of these parathyroid proliferations and their frequent association with familial disease.…”

Section: Pathology Of Hyperparathyroidismmentioning

confidence: 99%

“…The concept of parathyroid hyperplasia has been challenged with multiple studies showing clonal proliferation in otherwise traditional multiglandular parathyroid hyperplasias 16–21. This is supported by molecular studies evaluating parathyroid disease in multiple endocrine neoplasia type 1 (MEN1) and multiple endocrine neoplasia type 4 (MEN4) cohorts and tertiary HPTH, traditionally associated with multiglandular hyperplasia, which demonstrated clonal proliferations in the background of polyglandular hyperplasia 16–19,21–23. It has been reported that up to 25% of parathyroid hyperplasia are a manifestation of a familial syndrome 16–20,22.…”

Section: Pathology Of Hyperparathyroidismmentioning

confidence: 99%

“…[16][17][18][19][21][22][23] It has been reported that up to 25% of parathyroid hyperplasia are a manifestation of a familial syndrome. [16][17][18][19][20]22 As a result, the current WHO 2022 classification recommends the use of the term PHPTrelated multiglandular parathyroid disease which more accurately reflects the underlying molecular pathogenesis of these parathyroid proliferations and their frequent association with familial disease. The term hyperplasia has been reserved for the setting of secondary HPT.…”

Section: Pathology Of Hyperparathyroidismmentioning

confidence: 99%

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Advances and Updates in Parathyroid Pathology

Gokozan

Scognamiglio

2022

Advances in Anatomic Pathology

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Hyperparathyroidism is a common endocrine disorder characterized by elevated levels of parathyroid hormone and hypercalcemia and is divided into 3 types: primary, secondary, and tertiary. Distinction between these types is accomplished by correlation of clinical, radiologic, and laboratory findings with pathologic features. Primary hyperparathyroidism occurs sporadically in 85% of cases with the remaining cases associated with multiple familial syndromes. The pathologic manifestations of primary hyperparathyroidism include parathyroid adenoma, parathyroid hyperplasia, and parathyroid carcinoma. Recent advances in the understanding of the pathogenesis of parathyroid disease has helped to refine the diagnosis and classification of parathyroid lesions. The identification of multiple clonal proliferations in traditional multiglandular parathyroid hyperplasia has led to the adoption by the World Health Organization (WHO) of the alternate term of primary hyperparathyroidism-related multiglandular parathyroid disease. Additional nomenclature changes include the adoption of the term atypical parathyroid tumor in lieu of atypical parathyroid adenoma to reflect the uncertain malignant potential of these neoplasms. Clinical and morphologic features characteristic of familial disease have been described that can help the practicing pathologist identify underlying familial disease and provide appropriate management. Use of ancillary immunohistochemistry and molecular studies can be helpful in classifying parathyroid neoplasms. Parafibromin has proven useful as a diagnostic and prognostic marker in atypical parathyroid tumors and parathyroid carcinomas. This review provides an update on the diagnosis and classification of parathyroid lesions considering the recent advances in the understanding of the molecular and clinical features of parathyroid disease and highlights the use of ancillary studies (immunohistochemical, and molecular) to refine the diagnosis of parathyroid lesions.

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Section: Pathology Of Hyperparathyroidismmentioning

confidence: 99%

Section: Pathology Of Hyperparathyroidismmentioning

confidence: 99%

Section: Pathology Of Hyperparathyroidismmentioning

confidence: 99%

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Advances and Updates in Parathyroid Pathology

Gokozan

Scognamiglio

2022

Advances in Anatomic Pathology

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“…7,8 The pathogenesis of PA is not completely understood but can arise from either chief or oxyphil cells, representing different states of PTH-producing PGCs. 1,4,9,10 In some PAs, translocation of the CCND1 gene results in oncogenic upregulation of its protein product cyclin D1 that is essential for G1/S cell cycle transition, 6,8,9 while the mutational loss of tumour suppressor genes has also been found, including the genes MEN1, tumour protein 53 (TP53) and cyclin-dependent kinase inhibitor 1B (CDKN1B). [11][12][13][14] Moreover, epigenetic mechanisms have been identified to contribute to PA development and progression.…”

Section: Introductionmentioning

confidence: 99%

KMT2A and chronic inflammation as potential drivers of sporadic parathyroid adenoma

Xu,

La,

et al. 2024

Clinical & Translational Med

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BackgroundSporadic parathyroid adenoma (PA) is the most common cause of hyperparathyroidism, yet the mechanisms involved in its pathogenesis remain incompletely understood.MethodsSurgically removed PA samples, along with normal parathyroid gland (PG) tissues that were incidentally dissected during total thyroidectomy, were analysed using single‐cell RNA‐sequencing with the 10× Genomics Chromium Droplet platform and Cell Ranger software. Gene set variation analysis was conducted to characterise hallmark pathway gene signatures, and single‐cell regulatory network inference and clustering were utilised to analyse transcription factor regulons. Immunohistochemistry and immunofluorescence were performed to validate cellular components of PA tissues. siRNA knockdown and gene overexpression, alongside quantitative polymerase chain reaction, Western blotting and cell proliferation assays, were conducted for functional investigations.ResultsThere was a pervasive increase in gene transcription in PA cells (PACs) compared with PG cells. This is associated with high expression of histone‐lysine N‐methyltransferase 2A (KMT2A). High KMT2A levels potentially contribute to promoting PAC proliferation through upregulation of the proto‐oncogene CCND2, which is mediated by the transcription factors signal transducer and activator of transcription 3 (STAT3) and GATA binding protein 3 (GATA3). PA tissues are heavily infiltrated with myeloid cells, while fibroblasts, endothelial cells and macrophages in PA tissues are commonly enriched with proinflammatory gene signatures relative to their counterparts in PG tissues.ConclusionsWe revealed the previously underappreciated involvement of the KMT2A‒STAT3/GATA3‒CCND2 axis and chronic inflammation in the pathogenesis of PA. These findings underscore the therapeutic promise of KMT2A inhibition and anti‐inflammatory strategies, highlighting the need for future investigations to translate these molecular insights into practical applications.Highlights Single‐cell RNA‐sequencing reveals a transcriptome catalogue comparing sporadic parathyroid adenomas (PAs) with normal parathyroid glands. PA cells show a pervasive increase in gene expression linked to KMT2A upregulation. KMT2A‐mediated STAT3 and GATA3 upregulation is key to promoting PA cell proliferation via cyclin D2. PAs exhibit a proinflammatory microenvironment, suggesting a potential role of chronic inflammation in PA pathogenesis.

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“…Primary hyperparathyroidism (PHP), affecting 1-2% of individuals over 55 years of age, with females being more prone [1,2], encompasses a varied panel of presentations, from those easily treatable using a modern facelift approach, namely completely asymptomatic cases and even normocalcemic patterns (with incidental detection amid different biochemistry and endocrine screening protocols), to the challenging spectrum of familial/genetic PHP. This may display not only a more severe clinical manifestation, a higher risk of multi-glandular disease, and an onset at younger ages when compare to sporadic PHP but also the burden of distinct non-parathyroid comorbidities that lower the overall quality of life via endocrine and non-endocrine neoplasia [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Insights into Hyperparathyroidism–Jaw Tumour Syndrome: From Endocrine Acumen to the Spectrum of CDC73 Gene and Parafibromin-Deficient Tumours

Gheorghe,

Sima,

Florescu

et al. 2024

IJMS

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A total of 1 out of 10 patients with primary hyperparathyroidism (PHP) presents an underlying genetic form, such as multiple endocrine neoplasia types 1, 2A, etc., as well as hyperparathyroidism–jaw tumour syndrome (HJT). We aimed to summarise the recent data, thus raising more awareness regarding HJT, from the clinical perspective of PHP in association with the challenges and pitfalls of CDC73 genetic testing and parafibromin staining. This narrative review included a sample-focused analysis from the past decade according to a PubMed search. We identified 17 original human studies (≥4 patients per article). The mean age at disease onset was between 20.8 and 39.5 years, while the largest study found that 71% of patients had HJT recognised before the age of 30. Males and females seemed to be equally affected, in contrast with sporadic PHP. PHP represented the central manifestation of HJT, occurring as the first manifestation in up to 85% of HJT cases. A biochemistry panel found a mean serum calcium level above the level of 12 mg/dL in PHP. PTH was elevated in HJT as well, with average values of at least 236.6 pg/mL. The most frequent pathological type in PHP was a parathyroid adenoma, but the incidence of a parathyroid carcinoma was much higher than in non-HJT cases (15% of all parathyroid tumours), with the diagnosis being established between the age of 15 and 37.5. In some families up to 85% of carriers suffered from a parathyroid carcinoma thus indicating that certain CDC73 pathogenic variants may harbour a higher risk. An important issue in HJT was represented by the parafibromin profile in the parathyroid tumours since in HJT both parathyroid adenomas and carcinomas might display a deficient immunoreactivity. Another frequent manifestation in HJT was ossifying fibromas of the jaw (affecting 5.4% to 50% of patients; the largest study found a prevalence of 15.4%). HJT was associated with a wide variety of kidney lesion (mostly: kidney cysts, with a prevalence of up to 75%, and renal tumours involved in 19% of patients). The risk of uterine lesions seemed increased in HJT, especially with concern to leiomyomas, adenofibromas, and adenomyosis. The underlying pathogenic mechanisms and the involvement of CDC73 pathogenic variants and parafibromin expression are yet to be explored. Currently, the heterogeneous expression of parafibromin status and, the wide spectrum of CDC73 mutations including the variety of clinical presentations in HJT, make it difficult to predict the phenotype based on the genotype. The central role of HJT-PHP is, however, the main clinical element, while the elevated risk of parathyroid carcinoma requires a special awareness.

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Primary hyperparathyroidism: Disease of diverse genetic, symptomatic, and biochemical phenotypes

Cited by 7 publications

References 116 publications

Advances and Updates in Parathyroid Pathology

Advances and Updates in Parathyroid Pathology

KMT2A and chronic inflammation as potential drivers of sporadic parathyroid adenoma

Insights into Hyperparathyroidism–Jaw Tumour Syndrome: From Endocrine Acumen to the Spectrum of CDC73 Gene and Parafibromin-Deficient Tumours

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