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Center for Regenerative Medicine and Skeletal Development, Department of Reconstructive Sciences, University of Connecticut School of Dental Medicine, Farmington, Connecticut, USA
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Division of Endocrinology and Metabolism, University of Connecticut School of Medicine, Farmington, Connecticut, USA
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Objective
Primary hyperparathyroidism is most often caused by a sporadic single-gland parathyroid adenoma (PTA), a tumor type for which cyclin D1 is the only known and experimentally validated oncoprotein. However, the molecular origins of its frequent overexpression have remained mostly elusive. In this study, we explored a potential tumorigenic mechanism that could increase cyclin D1 stability through a defect in molecules responsible for its degradation.
Methods
We examined two tumor suppressor genes known to modulate cyclin D1 ubiquitination, PRKN and FBXO4 (FBX4), for evidence of classic two-hit tumor suppressor inactivation within a cohort of 82 PTA cases. We examined the cohort for intragenic inactivating and splice site mutations by Sanger sequencing and for locus-associated loss of heterozygosity (LOH) by microsatellite analysis.
Results
We identified no evidence of bi-allelic tumor suppressor inactivation of PRKN or FBXO4 via inactivating mutation or splice site perturbation, neither in combination with nor independent of LOH. Among the 82 cases, we encountered previously documented benign single nucleotide polymorphisms (SNPs) in 35 tumors at frequencies similar to those reported in the germlines of the general population. Eight cases exhibited intragenic LOH at the PRKN locus, in some cases extending to cover at least an additional 1.7 Mb of chromosome 6q25-26. FBXO4 was not affected by LOH.
Conclusion:
The absence of evidence for specific bi-allelic inactivation in PRKN and FBXO4 in this sizeable cohort suggests that these genes only rarely, if ever, serve as classic driver tumor suppressors responsible for the growth of PTAs.
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Background
Cutaneous lichen amyloidosis (CLA) has been reported in some multiple endocrine neoplasia type 2A (MEN 2A) families affected by specific germline RET mutations C634F/G/R/W/Y or V804M, as a characteristic of the clinical manifestation in ‘MEN 2A with CLA’, one of four variants of MEN 2A, which was strictly located in the scapular region of the upper back.
Patient Findings
This study reports a large south-eastern Chinese pedigree with 17 individuals carrying the MEN 2A-harboring germline C611Y (c.1832G>A) RET mutation by Sanger sequencing. One individual presented MEN 2A-related clinical features, including typical CLA in the interscapular region; another individual exhibited neurological pruritus and scratching in the upper back but lacked CLA skin lesions. Both subjects presented with CLA or pruritic symptoms several years before the onset of medullary thyroid carcinoma (MTC) and/or pheochromocytoma. The remaining 15 RET mutation carriers did not exhibit CLA; of these, one presented with MTC and pheochromocytoma, nine with MTC only, two with elevated serum calcitonin and three younger subjects with normal serum calcitonin levels. This family’s clinical data revealed a later diagnosis of MTC (mean age, 45.9 (range: 23–73) years), a lower penetrance of pheochromocytoma (2/17, 11.8%) and CLA (1/17, 5.9%). However, no hyperparathyroidism and Hirschsprung disease were reported in this family.
Summary and Conclusions
This is the first description of a family with MEN 2A-related CLA due to a germline RET C611Y mutation, which might exhibit a novel and diversified genotype–phenotype spectrum in MEN 2A.
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Background
Despite significant improvement in imaging quality and advanced scientific knowledge, it may still sometimes be difficult to distinguish different parathyroid lesions. The aims of this prospective study were to evaluate parathyroid lesions with ultrasound elastography and to determine whether strain index can help to differentiate parathyroid lesions.
Methods
Patients with biochemically confirmed hyperparathyroidism and localised parathyroid lesions in ultrasonography were included. All patients underwent B-mode US and USE examination. Ultrasound elastography scores and strain index of lesions were determined. Strain index was defined as the ratio of strain of the thyroid parenchyma to the strain of the parathyroid lesion.
Results
Data of 245 lesions of 230 patients were analysed. Histopathologically, there were 202 (82.45%) parathyroid adenomas, 26 (10.61%) atypical parathyroid adenomas, and 17 (6.94%) cases of parathyroid hyperplasia. Median serum Ca was significantly higher in atypical parathyroid adenoma patients than parathyroid hyperplasia patients (P = 0.019) and median PTH was significantly higher in APA compared to PA patients (P < 0.001). In 221 (90.2%) of the parathyroid lesions, USE score was 1 or 2. The median SI of atypical parathyroid adenomas was significantly higher than parathyroid adenomas and hyperplasia lesions (1.5 (0.56–4.86), 1.01 (0.21–8.43) and 0.91 (0.26–2.02), respectively, P = 0.003).
Conclusion
Our study revealed that SI of parathyroid lesions as well as serum calcium, parathyroid hormone levels, and B-mode US features may help to predict the atypical parathyroid adenoma. Ultrasound elastography can be used to differentiate among parathyroid lesions and guide a surgical approach.
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Institute of Clinical Endocrinology, Endocrinology Research Center, Moscow, Russian Federation
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Background
Primary hyperparathyroidism (PHPT) is a relatively rare disorder among children, adolescents and young adults. Its development at an early age is suspicious for hereditary causes, though the need for routine genetic testing remains controversial.
Objective
To identify and describe hereditary forms of PHPT in patients with manifestation of the disease under 40 years of age.
Design
We enrolled 65 patients with PHPT diagnosed before 40 years of age. Ten of them had MEN1 mutation, and PHPT in them was the first manifestation of multiple endocrine neoplasia type 1 syndrome.
Methods
The other fifty-five patients underwent next-generation sequencing (NGS) of a custom-designed panel of genes, associated with PHPT (MEN1, CASR, CDC73, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2C, CDKN2D). In cases suspicious for gross CDC73 deletions multiplex ligation-dependent probe amplification was performed.
Results
NGS revealed six pathogenic or likely pathogenic germline sequence variants: four in CDC73 c.271C>T (p.Arg91*), c.496C>T (p.Gln166*), c.685A>T (p.Arg229*) and c.787C>T (p.Arg263Cys); one in CASR c.3145G>T (p.Glu1049*) and one in MEN1 c.784-9G>A. In two patients, MLPA confirmed gross CDC73 deletions. In total, 44 sporadic and 21 hereditary PHPT cases were identified. Parathyroid carcinomas and atypical parathyroid adenomas were present in 8/65 of young patients, in whom CDC73 mutations were found in 5/8.
Conclusions
Hereditary forms of PHPT can be identified in up to 1/3 of young patients with manifestation of the disease at <40 years of age. Parathyroid carcinomas or atypical parathyroid adenomas in young patients are frequently associated with CDC73 mutations.
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Inactivating germline mutations of the CDKN1B gene encoding the nuclear cyclin-dependent kinase inhibitor P27kip1 protein have been reported in patients with multiple endocrine neoplasia type 4 (MEN4), a MEN1-like phenotype without MEN1 mutations. The aim of this study was to characterize in vitro the germline CDKN1B mutation c.374_375delCT (S125X) we detected in a patient with MEN4. The proband was affected by primary hyperparathyroidism due to multiglandular parathyroid involvement and gastro–entero–pancreatic tumors. We carried out subcellular localization experiments by transfection with plasmid vectors expressing the WT or mutant CDKN1B cDNA into the eukaryotic human cervix adenocarcinoma (HeLa) and GH3 cell lines. Results from western blotting studies indicated that fusion proteins were expressed at equal levels. The mutated protein was shorter compared with the WT protein and lacked the highly conserved C-terminal domain, which includes the bipartite nuclear localization signal at amino acids 152/153 and 166/168. In HeLa and GH3 cells, WT P27 localized in the nucleus, whereas the P27_S125X protein was retained in the cytoplasm, predicting the loss of tumor-suppressive function. The proband's tumoral parathyroid tissue did not show allelic loss, because both WT and mutant alleles were determined to be present by sequencing the somatic DNA. Immunohistochemistry revealed a complete loss of nuclear expression of P27 in a parathyroid adenoma, which had been removed by the second surgery in the patient. In conclusion, our results confirm the pathogenic role of the c.374_375delCT CDKN1B germline mutation in a patient with MEN4.
Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Primary hyperparathyroidism (PHPT) is a common endocrinopathy, frequently caused by a parathyroid adenoma, rarely by a parathyroid carcinoma that lacks effective oncological treatment. As the majority of cases are present in postmenopausal women, oestrogen signalling has been implicated in the tumourigenesis. Oestrogen receptor beta 1 (ERB1) and ERB2 have been recently identified in parathyroid adenomas, the former inducing genes coupled to tumour apoptosis. We applied immunohistochemistry and slide digitalisation to quantify nuclear ERB1 and ERB2 in 172 parathyroid adenomas, atypical adenomas and carcinomas, and ten normal parathyroid glands. All the normal parathyroid glands expressed ERB1 and ERB2. The majority of tumours expressed ERB1 (70.6%) at varying intensities, and ERB2 (96.5%) at strong intensities. Parathyroid carcinomas expressed ERB1 in three out of six cases and ERB2 in five out of six cases. The intensity of tumour nuclear ERB1 staining significantly correlated inversely with tumour weight (P=0.011), and patients whose tumours were classified as ERB1-negative had significantly greater tumour weight as well as higher serum calcium (P=0.002) and parathyroid hormone levels (P=0.003). Additionally, tumour nuclear ERB1 was not expressed differentially with respect to sex or age of the patient. Levels of tumour nuclear ERB2 did not correlate with clinical characteristics. In conclusion, decreased ERB1 immunoreactivity is associated with increased tumour weight in parathyroid adenomas. Given the previously reported correlation with tumour-suppressive signalling, selective oestrogen receptor modulation (SERMs) may play a role in the treatment of parathyroid carcinomas. Future studies of SERMs and oestrogen treatment in PHPT should consider tumour weight as a potential factor in pharmacological responsiveness.
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Department of Medical Genetics, Cambridge University, Cambridge, UK
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Primary hyperparathyroidism (pHPT) is a common endocrine disorder that can be cured by parathyroidectomy; patients unsuitable for surgery can be treated with cinacalcet. Availability of surgery may be reduced during COVID-19, and cinacalcet can be used as bridging therapy. In this single-centre retrospective analysis, we investigated the utility and safety of cinacalcet in patients with pHPT receiving cinacalcet between March 2019 and July 2020, including pre-parathyroidectomy bridging. We reviewed and summarised the published literature. Cinacalcet dosages were adjusted by endocrinologists to achieve target calcium < 2.70 mmol/L. Eighty-six patients were identified, with the most achieving target calcium (79.1%) with a mean dose of 39.4 mg/day (±17.1 mg/day) for a median duration of 35 weeks (1–178 weeks). Calcium was normalised in a median time of 5 weeks. The majority of patients commenced cinacalcet of 30 mg/day (78 patients) with the remainder at 60 mg/day (8 patients). Forty-seven patients commencing lower dose cinacalcet (30 mg/day) achieved target calcium without requiring 60 mg/day. Baseline PTH was significantly higher in patients requiring higher doses of cinacalcet. 18.6% of patients reported adverse reactions and 4.7% discontinued cinacalcet. Patients treated with cinacalcet pre-parathyroidectomy required a higher dose and fewer achieved target calcium compared to medical treatment with cinacalcet alone. Post-operative calcium was similar to patients who were not given pre-parathyroidectomy cinacalcet. In summary, cinacalcet at an initial dose of 30 mg/day is safe and useful for achieving target calcium in patients with symptomatic or severe hypercalcaemia in pHPT, including those treated for pre-parathyroidectomy. We propose a PTH threshold of >30 pmol/L to initiate at a higher dose of 60 mg/day.
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Background
The diagnosis of primary hyperparathyroidism (PHPT) remains a challenge because of increased asymptomatic PHPT or patients with normocalcaemic PHPT (NPHPT). In addition, some primary hospitals in China have no equipment to measure parathyroid hormone (PTH) levels. Therefore, an additional, simple, and inexpensive laboratory biochemical marker is urgently needed. The calcium/phosphate (Ca/P) ratio and chloride/phosphate (Cl/P) ratio have been proposed as suitable tools to diagnose PHPT in Europe; however, the Ca/P ratio has never been tested in China. We aimed to conduct a confirmatory study to explore the diagnostic performance of the Ca/P ratio for PHPT in China.
Methods
From January 2015 to December 2020, a total of 155 patients who underwent parathyroidectomy (143 PHPT patients and 12 NPHPT patients) and 153 controls were enrolled in this single-center , retrospective study. Serum calcium, phosphate, parathyroid hormone, 25-hydroxyvitamin vitamin D (25(OH) vitamin D), chloride, alanine transaminase (ALT), aspartate aminotransaminase (AST), estimated glomerular filtration rate (eGFR), and creatinine levels were recorded for all the study participants. Pairwise comparisons were made between groups, and the diagnostic performance of the Ca/P ratio was determined using receiver-operating characteristic (ROC) analysis.
Results
Patients with PHPT had a higher Ca/P ratio than controls (P < 0.001). A Ca/P ratio above 2.94 with a sensitivity of 95.5% and specificity of 98.7% can distinguish PHPT patients from healthy individuals. This index was positively correlated with the PTH level (r = 0.875, P < 0.001).
Conclusion
The Ca/P ratio is an ideal and inexpensive indicator for diagnosing PHPT in China when using a cut-off value of 2.94.
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Background
Multiple studies have reported the increased incidence of thyroid cancer in patients with primary hyperparathyroidism (PHPT). However, the underlying risk factors of concomitant thyroid cancer in patients with PHPT remain unknown. The primary aim of this study was to examine the records of patients with PHPT to identify characteristics that correlated with the presence of coexisting thyroid nodules, and which may have an implication for the prediction of thyroid cancer.
Methods
Medical records of consecutive patients with PHPT (n = 318) were reviewed from January 2010 to September 2020 in two tertiary medical centers in China. Patient clinicopathological and biological data were collected and analyzed.
Results
Of a total of 318 patients with PHPT, 105 (33.0%) patients had thyroid nodules and 26 (8.2%) patients were concomitant with thyroid cancer. A total of 38 thyroid nodules taken from 26 patients were pathologically assessed to be well-differentiated papillary thyroid carcinoma (PTC), with 81% being papillary thyroid microcarcinoma (PTMC). In 79% (30/38) of these cancers, thyroid nodules were considered suspicious following preoperative ultrasound. Multinomial logistic regression analysis revealed that female gender was associated with increased risk of thyroid nodules (OR = 2.13, 95% CI: 1.13–3.99, P = 0.019), while lower log-transformed parathyroid hormone levels were an independent predictor of thyroid cancer in patients with PHPT (OR = 0.50, 95% CI: 0.26–0.93, P = 0.028).
Conclusion
In conclusion, we observed a relatively high prevalence of thyroid cancer in our cohort of Chinese patients with PHPT. Evaluation of thyroid nodules by preoperative ultrasound may be advisable in patients with PHPT, particularly for females and patients with modestly elevated serum parathyroid hormone levels.
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Réseau TenGen, Marseille, France
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Fédération d’Endocrinologie, Hospices Civils de Lyon, Université Lyon 1, France
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Service de Génétique, AP-HP, Hôpital européen Georges Pompidou, Paris, France
Université de Paris, PARCC, INSERM, Paris, France
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Laboratoire de Biochimie et Oncologie Moléculaire, CHU Lille, Lille, France
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Laboratoire de Génétique Moléculaire, CHU Lyon, Lyon, France
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Department of Endocrinology, Assistance Publique-Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, Centre de Référence des Maladies Rares de l’hypophyse HYPO, Marseille, France
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Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
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Aix Marseille Univ, APHM, INSERM, MMG, Laboratory of Molecular Biology, Hospital La Conception, Marseille, France
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Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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Objective
Multiple endocrine neoplasia type 2A (MEN 2A) is a rare syndrome caused by RET germline mutations and has been associated with primary hyperparathyroidism (PHPT) in up to 30% of cases. Recommendations on RET screening in patients with apparently sporadic PHPT are unclear. We aimed to estimate the prevalence of cases presenting with PHPT as first manifestation among MEN 2A index cases and to characterize the former cases.
Design and methods
An international retrospective multicenter study of 1085 MEN 2A index cases. Experts from MEN 2 centers all over the world were invited to participate. A total of 19 centers in 17 different countries provided registry data of index cases followed from 1974 to 2017.
Results
Ten cases presented with PHPT as their first manifestation of MEN 2A, yielding a prevalence of 0.9% (95% CI: 0.4–1.6). 9/10 cases were diagnosed with medullary thyroid carcinoma (MTC) in relation to parathyroid surgery and 1/10 was diagnosed 15 years after parathyroid surgery. 7/9 cases with full TNM data were node-positive at MTC diagnosis.
Conclusions
Our data suggest that the prevalence of MEN 2A index cases that present with PHPT as their first manifestation is very low. The majority of index cases presenting with PHPT as first manifestation have synchronous MTC and are often node-positive. Thus, our observations suggest that not performing RET mutation analysis in patients with apparently sporadic PHPT would result in an extremely low false-negative rate, if no other MEN 2A component, specifically MTC, are found during work-up or resection of PHPT.
