Molecular Genetic Aspects of Sporadic Multiglandular Primary Hyperparathyroidism.

Multiglandular primary hyperparathyroidism (MGD) represents a rare form of primary hyperparathyroidism (PHPT). MGD is associated with hereditary PHPT, but the sporadic MGD is more common and affects a similar patient profile as single gland parathyroid disease (SGD). The distinction between SGD and MGD is of great clinical importance, especially for the strategy of parathyroidectomy. Based on the limited knowledge available, MGD is likely to be a genetically heterogeneous disease resulting from the interaction of germline and somatic DNA mutations together with epigenetic alterations. Furthermore, these events may combine and occur independently in parathyroid tumors within the same individual with MGD. Gene expression profiling has shown that SGD and MGD may represent distinct entities in parathyroid tumorigenesis. We are waiting for studies to analyze exactly which genes are different in SGD and MGD in order to identify potential biomarkers that can distinguish between the two forms of the disease.

Genetic testing for familial hyperparathyroidism: clinical-genetic profile in a Mediterranean cohort.

Background: Approximately 10% of primary hyperparathyroidism cases are hereditary, due to germline mutations in certain genes. Although clinically relevant, a systematized genetic diagnosis is missing due to a lack of firm evidence regarding individuals to test and which genes to evaluate. Methods: A customized gene panel (AIP, AP2S1, CASR, CDC73, CDKN1A, CDKN1B, CDKN2B, CDKN2C, GCM2, GNA11, MEN1, PTH, RET, and TRPV6) was performed in 40 patients from the Mediterranean area with suspected familial hyperparathyroidism (≤45 years of age, family history, high-risk histology, associated tumour, multiglandular disease, or recurrent hyperparathyroidism). We aimed to determine the prevalence of germline variants in these patients, to clinically characterize the probands and their relatives, and to compare disease severity in carriers versus those with a negative genetic test. Results: Germline variants were observed in 9/40 patients (22.5%): 2 previously unknown pathogenic/likely pathogenic variants of CDKN1B (related to MEN4), 1 novel variant of uncertain significance of CDKN2C, 4 variants of CASR (3 pathogenic/likely pathogenic variants and 1 variant of uncertain significance), and 2 novel variants of uncertain significance of TRPV6. Familial segregation studies allowed diagnosis and early treatment of PHPT in first-degree relatives of probands. Conclusion: The observed prevalence of germline variants in the Mediterranean cohort under study was remarkable and slightly higher than that seen in other populations. Genetic screening for suspected familial hyperparathyroidism allows the early diagnosis and treatment of PHPT and other related comorbidities. We recommend genetic testing for patients with primary hyperparathyroidism who present with high-risk features.

Spontaneous resolution of primary hyperparathyroidism post-biopsy-related neck haematoma.

Spontaneous or fine-needle aspiration (FNA)-induced remission of primary hyperparathyroidism (PHPT) is an extremely rare phenomenon with variable outcomes. We report a 75-year-old Male who initially presented with left ureteric calculi and was found to have PHPT. Imaging studies including ultrasound neck, parathyroid sestamibi scan and computed tomography of thorax, abdomen, and pelvis failed to identify the culprit lesion and exploratory parathyroidectomy was planned. Before surgery, he underwent FNA for cytology of a right cold thyroid nodule which was complicated with a large neck haematoma and dysphagia. The cytology of the aspirated fluid was consistent with a benign cyst. One month after the procedure, serum calcium and phosphate normalised along with resolution of haematoma. He remained in biochemical remission at 1-year follow-up with the latest ultrasound of neck showing resolution of a large colloid nodule that was previously seen occupying the right thyroid lobe.

Incremental value of 99m Tc-MIBI single-photon emission computed tomography/computed tomography fusion imaging for the diagnosis of secondary hyperparathyroidism.

PURPOSE: To assess the added value of 99m Tc-MIBI single-photon emission computed tomography/computed tomography (SPECT/CT) fusion imaging over dual-phase scintigraphy in the diagnosis of secondary hyperparathyroidism (SHPT). METHODS: This retrospective study included 23 patients with SHPT. The diagnostic efficacy of 99m Tc-MIBI dual-phase scintigraphy and SPECT/CT fusion imaging was analyzed and compared based on the result of postoperative pathology and follow-up. To evaluate the diagnostic ability of 99m Tc-MIBI dual-phase scintigraphy, the volume and radioactive count of parathyroid lesions were assessed using the region of interest method. RESULTS: A total of 79 hyperplastic parathyroid glands and two thyroid tissues were surgically removed from 23 SHPT patients and 13 normal parathyroid glands were preserved. 99m Tc-MIBI SPECT/CT fusion imaging showed higher sensitivity and accuracy than 99m Tc-MIBI dual-phase scintigraphy [sensitivity, 77.2% (61/79) vs 46.8% (37/79); accuracy, 80.4% (74/92) vs 54.3% (50/92), respectively], but comparable specificity [100% (13/13)). Among 61 positive lesions detected by 99m Tc-MIBI SPECT/CT fusion imaging, 37 were dual-phase scintigraphy positive and 24 were dual-phase scintigraphy false negative. The radioactivity counts and radioactivity per unit volume in dual-phase scintigraphy positive were higher than that in dual-phase scintigraphy false negative ( P  < 0.05), but the volume of parathyroid lesions between the two groups had no significant difference ( P  > 0.05). CONCLUSION: Compared with 99m Tc-MIBI dual-phase scintigraphy, 99m Tc-MIBI SPECT/CT fusion imaging has incremental value in the diagnosis of SHPT. The low uptake of MIBI in the whole gland and low MIBI uptake per unit volume are easy to cause dual-phase scintigraphy false negative.

Head-to-Head Comparison of Tc-99m-sestamibi SPECT/CT and C-11-L-Methionin PET/CT in Parathyroid Scanning Before Operation for Primary Hyperparathyroidism.

PURPOSE: The preferred nuclear medicine method for identification of hyperfunctioning parathyroid glands in hyperparathyroidism (HPT) develops continuously in relation to the technological progress. Diagnostic methods based on PET/CT have during recent years evolved with new tracer possibilities competing with traditional scintigraphic methods. This investigation is a head-to-head comparison of Tc-99m-sestamibi SPECT/CT gamma camera scintigraphy (sestamibi SPECT/CT) and C-11-L-methionin PET/CT imaging (methionine PET/CT) for preoperative identification of hyperfunctioning parathyroid glands. PROCEDURES: The study is a prospective cohort study including 27 patients diagnosed with primary hyperparathyroidism (PHPT). Two nuclear medicine physicians assessed all examinations independently and blinded. All scanning assessments were matched to the final surgical diagnosis as confirmed by histopathology. Biochemical monitoring of the therapeutical effects was performed preoperatively by PTH-measurements and followed postoperatively for up to 12 months. Comparisons were made for differences in sensitivity and positive predictive value (PPV). RESULTS: Twenty-seven patients (18 females, 9 males; mean age (range): 58.9 years (34.1-79)) were enrolled into the study. The 27 patients had a total of 33 identified sites of lesions of which 28 (85%) turned out to be histopathological verified hyperfunctioning parathyroid glands. The sensitivity and PPV for sestamibi SPECT/CT were 0.71 and 0.95; that of methionine PET/CT was 0.82 and 1, respectively. Both sensitivity and PPV were slightly lower for sestamibi SPECT/CT than for methionine PET PET/CT (-0.11, 95% confidence interval (95% CI): -0.29 to 0.08; -0.05, 95% CI: -0.14 to 0.04, respectively), but not to a statistically significant extent (p=0.38 and p=0.31). The sensitivity and PPV for diagnostic CT were 0.64 (95% CI: 0.44 to 0.81) and 1 (95% CI: 0.81 to 1). CONCLUSIONS: Methionine PET/CT performed comparable to sestamibi SPECT/CT with respect to identification and localization of hyperfunctioning parathyroid glands prior to surgery.

Rare duplication of the CDC73 gene and atypical hyperparathyroidism-jaw tumor syndrome: A case report and review of the literature.

BACKGROUND: Hyperparathyroidism jaw-tumor syndrome (HPT-JT) is the rarest familial cause of primary hyperparathyroidism, with an incidence <1/1000000, caused by a pathogenic variant in the CDC73 (or HRPT2) gene that encodes parafibromin, a protein involved in many cellular mechanisms. Patients with HPT-JT have a 15-20% of risk of developing parathyroid carcinoma, whereas it accounts for only 1% of all cases of primary hyperparathyroidism. Patients also develop jaw tumors in 30% of cases, kidney abnormalities in 15% of cases, and uterine tumors in 50% of patients. CASE REPORT: Here are report two atypical cases of HPT-JT with variable expressivity in the same family. In front of an isolated primary hyperparathyroidism at 28 years of age of incidental discovery following a weight gain, the propositus benefited a first-line panel by Next-Generation Sequencing of the genes involved in familial hyperparathyroidism: CaSR, CDC73, MEN1, and RET. Genetic testing revealed the presence of a pathogenic germline variation CDC73: c.687_688dup; p.Val230Glufs*28, found only in nine families in the literature and allowing the diagnosis of HPT-JT. Given a history of primary hyperparathyroidism at 52 years and adenomyosis, the patient's mother also underwent a genetic analysis that found her daughter's variation and established her inherited trait. CONCLUSION: In view of the clinical and genotypic heterogeneity, we confirm the interest of using an extended gene panel for the diagnosis of familial primary hyperparathyroidism. CDC73 variations could be more frequent than described in the literature. The association of primary hyperparathyroidism with uterine involvement could be a new indication for analysis.

Innate differences in the molecular signature of normal inferior & superior human parathyroid glands: potential implications for parathyroid adenoma.

Primary hyperparathyroidism is a common endocrine disorder. Interestingly, the majority (75%) of parathyroid tumors are localized to the inferior parathyroid glands. To date, the reason for this natural bias has not been investigated. We assessed the global gene expression profile of superior and inferior glands obtained from forensic autopsies. The genes with significant differential expression between superior and inferior parathyroids were further assessed by RT-PCR in 19 pairs. As an iterative approach, additional genes with an established role in parathyroid disorders, i.e., CASR, MAFB, PAX9, TBCE, TBX1, VDR, MEN1, CCND1, and CDC73 were also evaluated by RT-PCR in all 19 pairs of superior and inferior parathyroid glands. Seven homeobox genes, namely HOXA4, HOXA5, HOXBAS3, HOXB4, HOXB6, HOXB9, IRX1, and one encoding for ALDH1A2 showed a lower expression in the inferior parathyroid glands than in the superior. Conversely, SLC6A1 showed a higher expression in the inferior glands. Of the nine genes with significant differential mRNA expression among superior and inferior glands HOXB9, HOXB4 and IRX1 could be detected by western blotting/mass spectrometry. The study is the first to show the differential expression of nine genes HOXA4, HOXA5, HOXBAS3, HOXB4, HOXB6, HOXB9, IRX1, ALDH1A2, and SLC6A1 in inferior versus the superior parathyroid glands. This could have potential implications for the preferential localization of parathyroid tumors to the inferior parathyroid glands as observed in patients with primary hyperparathyroidism.

Opportunistic Parathyroid Gland Assessment on Routine CT Could Decrease Morbidity from Undiagnosed Primary Hyperparathyroidism.

RATIONALE AND OBJECTIVES: Gaps in primary hyperparathyroidism diagnosis are well-documented. End-organ damage correlates with disease duration and often occurs before diagnosis. We hypothesize that opportunistic parathyroid gland assessment on routine CT could decrease existing diagnosis gaps. Our purpose is to assess for enlarged parathyroid glands on contrast-enhanced CT acquired prior to biochemical screening and subsequent development of related morbidity. MATERIALS AND METHODS: This retrospective study included consecutive patients with primary hyperparathyroidism undergoing parathyroidectomy with contrast-enhanced CT including the lower neck and upper chest acquired prior to biochemical screening. One neuroradiologist retrospectively evaluated all CTs for enlarged (estimated weight greater than 60 mg) parathyroid glands. Gold standard operative and pathology reports were correlated with CT findings, and medical records were reviewed for development of primary hyperparathyroidism-related comorbidities. RESULTS: The sample comprised 38 patients (30 women, 8 men, median age 60 years) with 70 CTs of interest. The neuroradiologist identified 32 putative enlarged parathyroid glands (median estimated weight 307 mg) in 29 (76%) patients on CTs predating biochemical screening by a median of 30 months. Putative enlarged parathyroid glands on CT corresponded to pathologically proven parathyroid lesions in 26 (90%) patients. Of 26 patients with retrospectively identified pathologically proven parathyroid lesions, 12 (46%) developed at least 1 renal, bone, or neurocognitive comorbidity between CT and subsequent biochemical screening. CONCLUSION: Enlarged parathyroid glands are frequently visible on routine CTs acquired years prior to primary hyperparathyroidism diagnosis. Biochemical screening based on enlarged glands could potentially prevent associated morbidity in almost half of such patients.

Value of Old Imaging for Patients Undergoing Parathyroidectomy for Primary Hyperparathyroidism.

INTRODUCTION: Although imaging plays no role in diagnosing primary hyperparathyroidism (PHPT), preoperative localization is essential for a focused parathyroidectomy. We hypothesized that reviewing imaging obtained prior to PHPT diagnosis can identify enlarged parathyroid glands and provide information that might potentially impact the preoperative evaluation and intraoperative course of patients undergoing parathyroidectomy. METHODS: We included adult patients with PHPT who underwent parathyroidectomy between October 2015 and October 2020 and had contrast-enhanced computed tomography (CT) imaging of the lower neck and upper chest obtained prior to diagnosis for unrelated indications. A radiologist reviewed the prediagnosis CTs blinded to subsequent parathyroid localization imaging and operative findings. A surgeon assessed the radiologist's findings in the context of each case to determine the potential impact of information from old imaging on surgical decision-making. RESULTS: We identified at least one enlarged parathyroid gland on prior contrast-enhanced CT in 30 (75%) of 40 included patients. Despite old imaging enabling correct localization, 60% of these 30 underwent dedicated parathyroid imaging prior to parathyroidectomy. Knowledge of the enlarged parathyroid(s) on prior imaging might have allowed a more focused approach in 10.0% and prompted a more thorough exploration in 13.3%. In the total cohort, reviewing prior imaging could have provided information capable of changing the preoperative evaluation in 52.5% and the operative course in 17.5%. CONCLUSIONS: The identification of enlarged parathyroid glands on contrast-enhanced CT imaging that predates a diagnosis of PHPT is possible. Prospective studies might verify the impact of these findings on the preoperative evaluation and operative course of patients undergoing parathyroidectomy.

Advances and Updates in Parathyroid Pathology.

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.

Novel germline variants of CDKN1B and CDKN2C identified during screening for familial primary hyperparathyroidism.

PURPOSE: CDKN1B mutations were established as a cause of multiple endocrine neoplasia 4 (MEN4) syndrome in patients with MEN1 phenotype without a mutation in the MEN1 gene. In addition, variants in other cyclin-dependent kinase inhibitors (CDKIs) were found in some MEN1-like cases without the MEN1 mutation. We aimed to describe novel germline mutations of these genes in patients with primary hyperparathyroidism (PHPT). METHODS: During genetic screening for familial hyperparathyroidism, three novel CDKIs germline mutations in three unrelated cases between January 2019 and November 2021 were identified. In this report, we describe clinical features, DNA sequence analysis, and familial segregation studies based on these patients and their relatives. Genome-wide DNA study of loss of heterozygosity (LOH), copy number variation (CNV), and p27/kip immunohistochemistry was performed on tumour samples. RESULTS: DNA screening was performed for atypical parathyroid adenomas in cases 1 and 2 and for cystic parathyroid adenoma and young age at diagnosis of PHPT in case 3. Genetic analysis identified likely pathogenic variants of CDKN1B in cases 1 and 2 and a variant of the uncertain significance of CDKN2C, with uniparental disomy in the tumour sample, in case 3. Neoplasm screening of probands showed other non-endocrine tumours in case 1 (colon adenoma with dysplasia and atypical lipomas) and case 2 (aberrant T-cell population) and a non-functional pituitary adenoma in case 3. CONCLUSION: Germline mutations in CDKIs should be included in gene panels for genetic testing of primary hyperparathyroidism. New germline variants here described can be added to the current knowledge.

Application value of contrast-enhanced ultrasound in preoperative localization of microwave ablation for primary hyperparathyroidism.

BACKGROUND: Ultrasonography (US) and 99m Technetium-sestamibi scintigraphy (99m Tc-MIBI) are currently first-line imaging modalities to localize parathyroid adenomas with sensitivities of 80% and 84%, respectively. Therefore, finding other modalities to further improve the diagnostic accuracy for preoperative localization is critically needed. PURPOSE: To evaluate the application value of contrast-enhanced ultrasound (CEUS) in the preoperative localization of microwave ablation (MWA) for primary hyperparathyroidism (PHPT). METHODS: Between December 2012 and May 2021, 100 PHPT patients (34 males and 66 females; mean age, 56.31 ± 13.43 years; age range, 25-85 years) with 130 suspected parathyroid nodules were enrolled. US, CEUS, and 99m Tc-MIBI were performed for the localization of pathological parathyroid glands. All patients were performed MWA under ultrasound guidance. All the suspected parathyroid nodules underwent core needle biopsy under ultrasound guidance during MWA to confirm the pathology. The diagnostic performance of all the imaging tests was analyzed in comparison with the pathological results. RESULTS: A total of 130 nodules suspected to be of parathyroid origin from preoperative localization images were confirmed by pathological results, of which 116 were of parathyroid origin, and 14 were not of parathyroid origin. The sensitivity, specificity, accuracy, and the area under receiver operating characteristic curve of CEUS in the localization of pathological parathyroid glands were 100%, 92.86%, 99.23%, and 0.964, which were significantly higher than those of US (93.10%, 42.86%, 87.69%, and 0.680) and 99m Tc-MIBI (81.90%, 42.86%, 77.69%, and 0.624) (p < 0.05). The sensitivity and accuracy of CEUS were 100% and 97.22%, which were higher than those of 99m Tc-MIBI (65.62% and 63.89%) or US (75.00% and 72.22%) in patients with multiple parathyroid glands (p < 0.05). For smaller parathyroid adenomas (≤2 cm in diameter), the sensitivities of CEUS in locating hyperfunctioning parathyroid glands were 100%, which was significantly higher than that of 99m Tc-MIBI (73.68% and 84.31%, p < 0.05). CONCLUSIONS: CEUS is a valuable preoperative localization method for PHPT patients performed MWA, especially for the patients with smaller pathological parathyroid gland and multiple glandular lesions.

"Before skin incision" high-resolution ultrasound in primary hyperparathyroidism: a new imaging tool for surgeons?

PURPOSE: Various diagnostic methods have been utilized for localizing pathologic parathyroid glands to consequently provide the possibility of avoiding bilateral neck dissection in cases of primary hyperparathyroidism. Scintigraphy, combined with ultrasound, became established as the standard method of localization in the 2000s. The aim of this study was to evaluate the role of the "before skin incision" surgeon-performed ultrasound in determining the improvement in the diagnostic accuracy in a large case series. METHOD: The method used in this research is a retrospective observational study (study period: between 1-2014 and 12-2020) comparing two patient groups before (control group: 31 patients) and after (study group: 70 patients) the introduction of the ultrasonography surgical protocol: combined preoperative and "before skin incision" surgeon-performed ultrasound. RESULTS: The sensitivity of the combined preoperative "before skin incision" surgeon-performed ultrasound was 97%, and the positive predictive value was 93% in regard to detecting the number of diseased glands and the appropriate anatomic location (right versus left, upper versus lower). The sensitivity of the parathyroid scan (Tc-MIBI-scintigraphy) was 74%, and the positive predictive value was 92%. The duration of surgery was significantly shorter in the test group (84.7 vs. 66.4 min; Mann‒Whitney U: 0.006). No differences were detected between the two groups in regard to avoiding intraoperative or postoperative complications. CONCLUSION: The combination of the preoperative "before skin incision" surgeon-performed ultrasound could improve the efficiency of the preoperative location and anatomic classification using the standard literature-suggested diagnostic methods.

Smaller parathyroids have higher near-infrared autofluorescence intensity in hyperparathyroidism.

BACKGROUND: Intraoperative parathyroid gland identification can be challenging. Parathyroid glands have an intrinsic autofluorescence when excited by wavelengths in the near-infrared region. Studies using near-infrared cameras to detect parathyroid gland near-infrared autofluorescence have suggested improved identification. The pathologic parathyroid glands in primary hyperparathyroidism have variable near-infrared autofluorescence intensity, but how this correlates with different characteristics of hyperparathyroidism is unknown. Our objective was to correlate the fluorescent intensity of excited glands with clinical variables to enhance a surgeon's ability to identify parathyroid glands. METHODS: The data on patients undergoing surgery for primary hyperparathyroidism were collected. The images were collected intraoperatively with a handheld near-infrared device and analyzed. The data consisted of the ratio of mean parathyroid gland near-infrared autofluorescence over background (white gauze) near-infrared autofluorescence. The variables assessed for correlation with autofluorescence intensity were gland volume and weight, preoperative serum calcium and parathyroid hormone, age, body mass index, and sex. The images were quantified by Image J software (National Institutes of Health, Bethesda, MD). The lasso regression was analyzed by R version 4.1.3 to calculate adjusted P values (R Foundation for Statistical Computing, Vienna, Austria). RESULTS: From 2017 to 2021, 131 patients with primary hyperparathyroidism underwent parathyroidectomies of 151 parathyroid glands. The mean near-infrared autofluorescence intensity of parathyroid glands had a negative correlation with weight with lighter glands fluorescing more (P = .019) and a positive correlation with age with glands from older patients fluorescing more (P = .013). There were no significant correlations with preoperative serum calcium and parathyroid hormone, body mass index, and sex (P > .05). CONCLUSION: In patients with primary hyperparathyroidism, we found that autofluorescence intensity correlated with parathyroid gland weight and patient age. This suggested that near-infrared camera use may be particularly helpful in identifying smaller adenomas and in older patients.

Multilevel Annotation of Germline MEN1 Variants of Synonymous, Nonsynonymous, and Uncertain Significance in Indian Patients With Sporadic Primary Hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is third most common endocrine disorder characterized by hypercalcemia with elevated or nonsuppressed parathyroid hormone levels by parathyroid tumors. Familial PHPT, as part of multiple endocrine type-1, occurs due to the germline mutation in the MEN1 gene. The involvement and the role of germline MEN1 variations in sporadic PHPT of Indian PHPT patients are unknown. Precise classifications of different types of MEN1 variations are fundamental for determining clinical relevance and diagnostic role. This prospective cohort study was performed on 82 patients with PHPT (with no clinical or history of MEN1) who underwent screening for MEN1 variations through Sanger sequencing. Multilevel computational analysis was performed to determine the structure-function relationship of synonymous, nonsynonymous, and variants of uncertain significance (VUS). Of the 82 PHPT patients, 42 (51%) had 26 germline MEN1 variants, including eight nonsynonymous, seven synonymous, nine VUS, one splice site, and one regulatory variation. Five most common germline variations (c.1838A>G, c.1817C>T, c.1525C>A, c.-35A>T, and c.250T>C) were observed in this study. c.-35A>T (5' untranslated region [UTR]) was associated with recurrence of PHPT (odds ratio [OR] = 5.4; p = 0.04) and subsequent detection of other endocrine tumors (OR = 13.6, p = 0.035). c.1525C>A was associated with multi glandular parathyroid tumor (OR = 13.6, p = 0.035). Align-Grantham variation and Grantham deviation (Align-GVGD), functional analysis through hidden Markov MODEL (FATHMM), and MutationTaster analysis reported the disease-specific potential of VUS and synonymous variations. Significant linkage disequilibrium was observed in c.1785G>A and c.1817C>T (r2  = 0.3859, p = 0.0001), c.1475C>G and c.1525C>A (r2  = 0.385, p = 0.0004), and c.1569T>C and c.1838A>G (r2  = 0.488, p = 0.0001). The detection of MEN1 variations, especially those with disease-specific potential, can prompt early screening for other MEN1-related tumors and disease recurrence. © 2022 American Society for Bone and Mineral Research (ASBMR).

Accuracy of Parathyroid Adenoma Localization by Preoperative Ultrasound and Sestamibi in 1089 Patients with Primary Hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (pHPT) is well treatable surgically. Sonography (US) and sestamibi scintigraphy (MIBI) are used routinely, but it is unclear how valuable they are in determining Parathyroid glands' different locations. This study aimed to evaluate the prognostic value of US and MIBI in relation to the different localization of parathyroid adenomas in one of the largest study populations analyzed to date. METHODS: 1089 patients with pHPT who had treatment in one tertiary referral center between 2007 and 2016 were analyzed. Preoperative US and MIBI reports were compared with the parathyroid adenoma's intraoperative localization. All parathyroid glands were confirmed by histological diagnosis. RESULTS: No gland was detectable in 22.5% and 27.7% of all patients, by US or by MIBI, respectively. In relation to the different adenoma locations, the sensitivity of US ranged from 21.3% (upper right) to 68.9% (lower left) and of MIBI ranged from 23.5% (upper right) to 72% (lower left). The specificity for US ranged from 85% (lower right) to 99.2% (upper right) and for MIBI ranged from 86.1% (lower right) to 99.1% (upper right. Positive predictive values for all gland sites were 54% and 59% for MIBI and US, respectively. The value increased for side-only prediction to 73% and 78%, respectively. Neither the parathyroid hormone level nor the calcium value level influenced the sensitivity or specificity of the two test methods. CONCLUSIONS: The validity of preoperative US and MIBI depends crucially on the specific localization of adenomas. This should be considered when planning the extent of parathyroid surgery.

Implications of regulator of G-protein signaling 5 expression in the pathogenesis of primary and secondary hyperparathyroidism.

OBJECTIVE: To study the protein and mRNA expressions of regulator of G-protein signaling 5 (RGS5) in the pathogenesis of hyperparathyroidism. METHODS: The expression of RGS5 protein in 20 primary hyperparathyroidism (PHPT), 31 secondary hyperparathyroidism (SHPT), and 20 control cases were studied by immunohistochemistry (IHC). The expression of RGS5 mRNA in 15 PHPT, 102 SHPT, and 7 normal parathyroid tissue were measured by quantitative real-time PCR (qRT-PCR) method. RESULTS: The expressions of RGS5 in PHPT tissues were significantly higher than that in SHPT and normal parathyroid tissues (P < 0.05). While the differences in RGS5 protein expressions between SHPT and respective control samples were not statistically significant (P > 0.05). Likewise, the RGS5 mRNA expression in PHPT was significantly higher than that in SHPT (P < 0.05) and normal parathyroid (P < 0.05) samples. In a similar line, the differences in RGS5 gene expressions between SHPT and control tissues were not statistically significant (P > 0.05). CONCLUSIONS: The characteristic RGS5 protein and mRNA levels in hyperparathyroidism might be helpful in discovering the pathomechanism of hyperparathyroidism and novel therapeutic targets as well.

Genotype-Phenotype Correlations in Asian Indian Children and Adolescents with Primary Hyperparathyroidism.

Childhood and adolescent primary hyperparathyroidism (PHPT) is a very rare disease. Data on its molecular genetics are scarce. We performed a retrospective analysis (January 2000-January 2021) to determine the deleterious germline variants and genotype-phenotype correlations in children and adolescents < 20 years diagnosed with PHPT from a single referral center. Clinical features, biochemistry, imaging, management, and genetics (clinical exome analyzed for 11 PHPT and 7 pancreatitis-associated genes, MLPA for CDC73) were recorded. Thirty-six patients (20 males; median age 17 years) were classified into those with familial and/or syndromic (F/S) or apparently sporadic (AS) presentation. Sixteen (44.4%) harbored pathogenic/likely pathogenic germline variants in PHPT-associated genes. The genetic yield in F/S group was 90% (MEN1:8/10; CDC73:1/10), and AS group was 26.9% (CDC73:4/26; CASR:3/26). F/S group had frequent asymptomatic presentation (60% vs none; P < 0.001), lower serum PTH (237.5 vs 1369.1 pg/mL; P = 0.001), and maximum parathyroid dimension (0.9 vs 2.2 cm; P = 0.01) than AS group. Among the AS group, renal involvement was higher in those with molecular diagnoses (71.4% vs 10.5%; P = 0.01). All those with novel CASR variants (including one homozygous) had hypercalciuria and histology-proven parathyroid adenoma/carcinoma. A missense CTRC VUS occurred in one patient with chronic pancreatitis. In summary, Asian Indian children and adolescents with PHPT have high genetic yield, even with apparently sporadic presentation. The phenotypic spectrum of CASR variants is expanded to include childhood/adolescent PHPT with hypercalciuria and single gland neoplasia. The proposed roles for renal involvement to predict molecular diagnosis among those with apparently sporadic presentation require further elucidation.

Percentage arterial enhancement on 2D CT in the diagnosis of primary hyperparathyroidism: A prospective validation study and potential pitfalls.

BACKGROUND: Parathyroid lesions are identified by subjective enhancement and washout patterns on computed tomography (CT). We have previously proposed "percentage arterial enhancement" (PAE) as an objective index and now aim to validate its performance prospectively. METHODS: Dual-phase CT was performed in 40 consecutive primary hyperparathyroidism patients. PAE was calculated as [{arterial phase Hounsfield unit (HU)-unenhanced phase HU}/unenhanced phase HU] × 100. PAE > 128.9% was considered parathyroid. RESULTS: PAE had 94.2% sensitivity, 100% positive predictive value (PPV) in lateralization, and sensitivity and PPV of 93.9% in quadrant localization of single-gland disease. PAE failed to identify two lesions: an intrathyroidal parathyroid carcinoma in the background of multinodular goiter and another lower enhancing cystic parathyroid adenoma. PAE had 60% sensitivity, and 100% PPV to identify multigland disease. The mean effective dose was 2.74 mSV. CONCLUSIONS: PAE is a specific CT index for parathyroid lesions with less radiation exposure. Areas of caution include intrathyroidal and cystic lesions.

Parathyroid venous sampling for the preoperative localisation of parathyroid adenoma in patients with primary hyperparathyroidism.

Preoperative localisation studies are essential for parathyroidectomy in patients with primary hyperparathyroidism. If the location of abnormal parathyroid glands cannot be identified through non-invasive studies, parathyroid venous sampling (PVS) may be employed. In this study, we evaluated the utility of preoperative PVS in parathyroid surgery. Patients with primary hyperparathyroidism who underwent preoperative PVS at Severance Hospital between January 2015 and June 2020 were identified. Patients for whom the results of non-invasive imaging studies were inconsistent or negative underwent PVS. The results of PVS were compared with operative findings and pathologic results. For 14 patients, the results of preoperative ultrasonography and 99mTc-sestamibi single-photon emission computed tomography (SPECT) were negative; for 20 patients, either the result of only one test was positive, or the results of the two tests were inconsistent. With respect to the lateralisation of diseased adenoma, the results of PVS and pathological examination were inconsistent only for one patient in either group (total: 2/34 patients). This study showed that PVS could be used effectively for preoperative localisation in patients with primary hyperparathyroidism in whom the location of diseased parathyroid glands cannot be determined through non-invasive image studies.