Sporadic parathyroid adenoma: an updated review of molecular genetics

Chorti, Angeliki; Cheva, Angeliki; Chatzikyriakidou, Anthoula; Achilla, Charoula; Boulogeorgou, Kassiani; Despoina, Krokou; Milias, Stefanos; Zarampoukas, Thomas; Papavramidis, Theodossis

doi:10.3389/fendo.2023.1180211

Cited by 6 publications

(3 citation statements)

References 41 publications

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“…( 39 ) Documented cases of primary hyperparathyroidism and missense p.Arg396Trp mutation raise the question of whether the described genetic alteration predisposes patients to parathyroid autonomy. The link between loss-of-function CYP24A1 mutations and the development of primary hyperparathyroidism has not been confirmed ( 50 ). In the present case, a heterozygous missense variant (rs114368325; p.Arg396Trp) was also identified, together with the second pathogenic variant.…”

Section: Discussionmentioning

confidence: 99%

Persistent hypercalcaemia associated with two pathogenic variants in the CYP24A1 gene and a parathyroid adenoma—a case report and review

Leszczyńska,

Szatko,

Latocha

et al. 2024

Front. Endocrinol.

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Introduction24-Hydroxylase, encoded by the CYP24A1 gene, is a crucial enzyme involved in the catabolism of vitamin D. Loss-of-function mutations in CYP24A1 result in PTH-independent hypercalcaemia with high levels of 1,25(OH)2D3. The variety of clinical manifestations depends on age, and underlying genetic predisposition mutations can lead to fatal infantile hypercalcaemia among neonates, whereas adult symptoms are usually mild.Aim of the studyWe report a rare case of an adult with primary hyperparathyroidism and loss-of-function mutations in the CYP24A1 gene and a review of similar cases.Case presentationWe report the case of a 58-year-old woman diagnosed initially with primary hyperparathyroidism. Preoperatively, the suspected mass adjoining the upper pole of the left lobe of the thyroid gland was found via ultrasonography and confirmed by 99mTc scintigraphy and biopsy as the parathyroid gland. The patient underwent parathyroidectomy (a histopathology report revealed parathyroid adenoma), which led to normocalcaemia. After 10 months, vitamin D supplementation was introduced due to deficiency, and the calcium level remained within the reference range. Two years later, biochemical tests showed recurrence of hypercalcaemia with suppressed parathyroid hormone levels and elevated 1,25(OH)2D3 concentrations. Further investigation excluded the most common causes of PTH-independent hypercalcaemia, such as granulomatous disease, malignancy, and vitamin D intoxication. Subsequently, vitamin D metabolites were measured using LC–MS/MS, which revealed high levels of 25(OH)D3, low levels of 24,25(OH)2D3 and elevated 25(OH)2D3/24,25(OH)2D3 ratios, suggesting a defect in vitamin D catabolism. Molecular analysis of the CYP24A1 gene using the NGS technique revealed two pathogenic variants: p.(Arg396Trp) and p.(Glu143del) (rs114368325 and rs777676129, respectively).ConclusionsThe diagnostic process for hypercalcaemia becomes complicated when multiple causes of hypercalcaemia coexist. The measurement of vitamin D metabolites using LC–MS/MS may help to identify carriers of CYP24A1 mutations. Subsequent molecular testing may contribute to establishing the exact frequency of pathogenic variants of the CYP24A1 gene and introducing personalized treatment.

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Section: Discussionmentioning

confidence: 99%

Persistent hypercalcaemia associated with two pathogenic variants in the CYP24A1 gene and a parathyroid adenoma—a case report and review

Leszczyńska,

Szatko,

Latocha

et al. 2024

Front. Endocrinol.

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“… 70 , 71 Therefore, it is likely that the increase in CCND2 similarly plays a driving role in PA pathogenesis. The upregulation of CCND1 in PACs is commonly due to chromosomal translocation or gene amplification, 48 , 72 but the cause of increased CCND2 expression requires further study. Regardless, our results suggested the possible involvement of GATA3 and STAT3 in transcriptional activation of CCND2 .…”

Section: Discussionmentioning

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 is a common endocrine disorder, affecting approximately 1% of the overall population. [ 1 ] This is characterized by excessive production of parathyroid hormone (PTH) due to an overactive parathyroid gland, leading to a significant increase in serum calcium levels. [ 2 ] It is caused by a sporadic parathyroid adenoma (80%–85%), multiglandular parathyroid hyperplasia (15%–20%), or parathyroid carcinoma (<0.5%).…”

Section: Introductionmentioning

confidence: 99%

Incidentally detected follicular thyroid carcinoma mimicking parathyroid adenoma on Tc-99m MIBI scan: A case report

Han,

Jeong,

Lee

et al. 2024

Medicine

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Rationale: Primary hyperparathyroidism, though relatively prevalent among endocrine disorders, affecting 1% of the general population, often presents diagnostic challenges. Given its potential to precipitate severe complications including nephrolithiasis and fractures, timely diagnosis, and effective management are crucial. Patient concerns: A 38-year-old woman with hypercalcemia was referred to the Department of Nuclear Medicine for a Tc-99m MIBI scan. Diagnoses: Tc-99m MIBI scan showed focal increased uptake in the left thyroid gland area, initially suggesting a parathyroid adenoma. Further examination using SPECT/CT revealed a nodular lesion within the left thyroid gland showing high Tc-99m MIBI uptake. Interventions: Left thyroid lumpectomy confirmed the lesion as follicular thyroid carcinoma. On the second Tc-99m MIBI scan conducted after total thyroidectomy, a parathyroid adenoma was eventually detected in the right lower area, enabling the subsequent appropriate treatment, a right lower parathyroidectomy. Outcomes: Thirteen days after the parathyroidectomy, serum levels of total calcium and parathyroid hormone returned to normal. Furthermore, bone mineral density evaluated using DEXA remained within the expected range for her age even after 14 months. Lessons: When interpreting the Tc-99m MIBI scan, it is essential to keep in mind that various tumors rich in mitochondria, such as thyroid carcinoma, could show a high uptake of Tc-99m MIBI.

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Sporadic parathyroid adenoma: an updated review of molecular genetics

Cited by 6 publications

References 41 publications

Persistent hypercalcaemia associated with two pathogenic variants in the CYP24A1 gene and a parathyroid adenoma—a case report and review

Persistent hypercalcaemia associated with two pathogenic variants in the CYP24A1 gene and a parathyroid adenoma—a case report and review

KMT2A and chronic inflammation as potential drivers of sporadic parathyroid adenoma

Incidentally detected follicular thyroid carcinoma mimicking parathyroid adenoma on Tc-99m MIBI scan: A case report

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