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Shu-Meng Hu Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

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Yang-Juan Bai Department of Laboratory Medicine/Research Centre of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China

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Ya-Mei Li Department of Laboratory Medicine/Research Centre of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China

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Ye Tao Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

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Xian-Ding Wang Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

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Tao Lin Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

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Lan-Lan Wang Department of Laboratory Medicine/Research Centre of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China

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Yun-Ying Shi Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

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Introduction

Tertiary hyperparathyroidism (THPT) and vitamin D deficiency are commonly seen in kidney transplant recipients, which may result in persistently elevated fibroblast growth factor 23 (FGF23) level after transplantation and decreased graft survival. The aim of this study is to evaluate the effect of vitamin D supplementation on THPT, FGF23-alpha Klotho (KLA) axis and cardiovascular complications after transplantation.

Materials and methods

Two hundred nine kidney transplant recipients were included and further divided into treated and untreated groups depending on whether they received vitamin D supplementation. We tracked the state of THPT, bone metabolism and FGF23–KLA axis within 12 months posttransplant and explored the predictors and risk factors for intact FGF23 levels, KLA levels, THPT and cardiovascular complications in recipients.

Results

Vitamin D supplementation significantly improved FGF23 resistance, THPT and high bone turnover status, preserved better graft function and prevented coronary calcification in the treated group compared to the untreated group at month 12. The absence of vitamin D supplementation was an independent risk factor for THPT and a predictor for intact FGF23 and KLA levels at month 12. Age and vitamin D deficiency were independent risk factors for coronary calcification in recipients at month 12.

Conclusion

Vitamin D supplementation effectively improved THPT, FGF23 resistance and bone metabolism, preserved graft function and prevented coronary calcification after transplantation.

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Julie Wulf Christensen Department of Nuclear Medicine, Herlev and Gentofte Hospital, Herlev, Denmark

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Karin Folmer Thøgersen Department of Nuclear Medicine, Herlev and Gentofte Hospital, Herlev, Denmark

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Lars Thorbjørn Jensen Department of Nuclear Medicine, Herlev and Gentofte Hospital, Herlev, Denmark

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Martin Krakauer Department of Nuclear Medicine, Herlev and Gentofte Hospital, Herlev, Denmark
Department of Clinical Physiology and Nuclear Medicine, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark

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Bent Kristensen Department of Nuclear Medicine, Herlev and Gentofte Hospital, Herlev, Denmark

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Finn Noe Bennedbæk Division of Endocrinology, Department of Medicine, Herlev and Gentofte Hospital, Herlev, Denmark

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Bo Zerahn Department of Nuclear Medicine, Herlev and Gentofte Hospital, Herlev, Denmark

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Objective

The extent of symptoms due to primary hyperparathyroidism (PHPT) depends on the population being studied. PHPT is mainly discovered incidentally through routine laboratory findings. Less is known about patient-experienced improvement following successful parathyroidectomy. The aim of our study was to assess the changes in the quality of life (QoL) after successful surgery using an SF-36 questionnaire.

Design

This is a prospective cohort study based on questionnaires.

Methods

Forty consecutive patients diagnosed with PHPT were prospectively administered an SF-36 questionnaire before and 6 months after successful parathyroidectomy. A subgroup of 18 patients answered the questionnaire at 1 and 3 months after surgery. Successful surgery was based on biochemistry and pathology reports as confirmed by an endocrinologist. Results of each SF-36 subcategory were compared to the results at baseline in order to detect changes in patient-reported QoL after successful surgery.

Results

There were significant improvements in six of eight SF-36 subcategories: vitality (P = 0.0001), physical functioning (P = 0.04), general health perception (P = 0.004), physical role functioning (P = 0.04), social role functioning (P = 0.004), and mental health perception (P = 0.0001). Changes appeared within a month after surgery with no further significant changes at later time points.

Conclusions

Parathyroidectomy significantly improves QoL as measured by a decrease in SF-36 scores as early as 1 month after successful parathyroidectomy. The SF-36 QoL questionnaire is suitable for monitoring changes in patient well-being after successful parathyroidectomy.

Open access
Marcela Moraes Mendes Department of Nutrition, Faculty of Health Sciences, University of Brasília, Distrito Federal, Brazil
Department of Nutrition, Institute of Life Sciences, Federal University of Juiz de Fora, Governador Valadares, Minas Gerais, Brazil
Department of Nutrition, Faculty of Health and Medical Sciences, University of Surrey, University of Surrey, Guildford, UK

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Patricia Borges Botelho Department of Nutrition, Faculty of Health Sciences, University of Brasília, Distrito Federal, Brazil

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Helena Ribeiro Department of Environmental Health, Faculty of Public Health, University of São Paulo, São Paulo, Brazil

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Vitamin D enhances calcium absorption and bone mineralisation, promotes maintenance of muscle function, and is crucial for musculoskeletal health. Low vitamin D status triggers secondary hyperparathyroidism, increases bone loss, and leads to muscle weakness. The primary physiologic function of vitamin D and its metabolites is maintaining calcium homeostasis for metabolic functioning, signal transduction, and neuromuscular activity. A considerable amount of human evidence supports the well-recognised contribution of adequate serum 25-hydroxyvitamin D concentrations for bone homeostasis maintenance and prevention and treatment strategies for osteoporosis when combined with adequate calcium intake. This paper aimed to review the literature published, mainly in the last 20 years, on the effect of vitamin D and its supplementation for musculoskeletal health in order to identify the aspects that remain unclear or controversial and therefore require further investigation and debate. There is a clear need for consistent data to establish realistic and meaningful recommendations of vitamin D status that consider different population groups and locations. Moreover, there is still a lack of consensus on thresholds for vitamin D deficiency and optimal status as well as toxicity, optimal intake of vitamin D, vitamin D supplement alone as a strategy to prevent fractures and falls, recommended sun exposure at different latitudes and for different skin pigmentations, and the extra skeletal effects of vitamin D.

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Sara Lomelino Pinheiro Serviço de Endocrinologia, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

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Ana Saramago Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

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Branca Maria Cavaco Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

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Carmo Martins Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

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Valeriano Leite Serviço de Endocrinologia e Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

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Tiago Nunes da Silva Serviço de Endocrinologia e Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

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Nineteen cases of parathyroid carcinoma in patients with multiple endocrine neoplasia type 1 have been reported in the literature, of which 11 carry an inactivating germline mutation in the MEN1 gene. Somatic genetic abnormalities in these parathyroid carcinomas have never been detected. In this paper, we aimed to describe the clinical and molecular characterization of a parathyroid carcinoma identified in a patient with MEN1. A 60-year-old man was diagnosed with primary hyperparathyroidism during the postoperative period of lung carcinoid surgery. Serum calcium and parathyroid hormone levels were 15.0 mg/dL (8.4–10.2) and 472 pg/mL (12–65), respectively. The patient underwent parathyroid surgery, and histological findings were consistent with parathyroid carcinoma. Analysis of the MEN1 gene by next-generation sequencing (NGS) identified a novel germline heterozygous nonsense pathogenic variant (c.978C>A; p.(Tyr326*)), predicted to encode a truncated protein. Genetic analysis of the parathyroid carcinoma revealed a c.307del, p.(Leu103Cysfs*16) frameshift truncating somatic MEN1 variant in the MEN1 gene, which is consistent with MEN1 tumor-suppressor role, confirming its involvement in parathyroid carcinoma etiology. Genetic analysis of CDC73, GCM2, TP53, RB1, AKT1, MTOR, PIK3CA and CCND1 genes in the parathyroid carcinoma DNA did not detect any somatic mutations. To our knowledge, this is the first report of a PC case presenting both germline (first-hit) and somatic (second-hit) inactivation of the MEN1 gene.

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Kelly Brewer Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut, USA

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Isabel Nip Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut, USA

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Justin Bellizzi Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut, USA

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Jessica Costa-Guda Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut, USA
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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Andrew Arnold Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut, USA
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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Laura J Reid Edinburgh Centre for Endocrinology and Diabetes, Royal Infirmary of Edinburgh, Edinburgh, UK

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Bala Muthukrishnan Edinburgh Centre for Endocrinology and Diabetes, Royal Infirmary of Edinburgh, Edinburgh, UK

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Dilip Patel Department of Radiology, Royal Infirmary of Edinburgh, Edinburgh, UK

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Mike S Crane Department of Clinical Biochemistry, Royal Infirmary of Edinburgh, Edinburgh, UK

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Murat Akyol Department of Surgery, Royal Infirmary of Edinburgh, Edinburgh, UK

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Andrew Thomson Department of Pathology, Royal Infirmary of Edinburgh, Edinburgh, UK

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Jonathan R Seckl Edinburgh Centre for Endocrinology and Diabetes, Royal Infirmary of Edinburgh, Edinburgh, UK
Centre for Cardiovascular Science, Queen’s Medical Research Unit, University of Edinburgh, Edinburgh, UK

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Fraser W Gibb Edinburgh Centre for Endocrinology and Diabetes, Royal Infirmary of Edinburgh, Edinburgh, UK

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Objective

Primary hyperparathyroidism (PHPT) is a common reason for referral to endocrinology but the evidence base guiding assessment is limited. We evaluated the clinical presentation, assessment and subsequent management in PHPT.

Design

Retrospective cohort study.

Patients

PHPT assessed between 2006 and 2014 (n = 611) in a university hospital.

Measurements

Symptoms, clinical features, biochemistry, neck radiology and surgical outcomes.

Results

Fatigue (23.8%), polyuria (15.6%) and polydipsia (14.9%) were associated with PHPT biochemistry. Bone fracture was present in 16.4% but was not associated with biochemistry. A history of nephrolithiasis (10.0%) was associated only with younger age (P = 0.006) and male gender (P = 0.037). Thiazide diuretic discontinuation was not associated with any subsequent change in calcium (P = 0.514). Urine calcium creatinine clearance ratio (CCCR) was <0.01 in 18.2% of patients with confirmed PHPT. Older age (P < 0.001) and lower PTH (P = 0.043) were associated with failure to locate an adenoma on ultrasound (44.0% of scans). When an adenoma was identified on ultrasound the lateralisation was correct in 94.5%. Non-curative surgery occurred in 8.2% and was greater in those requiring more than one neck imaging modality (OR 2.42, P = 0.035).

Conclusions

Clinical features associated with PHPT are not strongly related to biochemistry. Thiazide cessation does not appear to attenuate hypercalcaemia. PHPT remains the likeliest diagnosis in the presence of low CCCR. Ultrasound is highly discriminant when an adenoma is identified but surgical failure is more likely when more than one imaging modality is required.

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Xiao-Ping Qi Department of Oncologic and Urologic Surgery, The 117th PLA Hospital, Wenzhou Medical University, Hangzhou, Zhejiang Province, China

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Jian-Zhong Peng Department of Dermatology, Hangzhou Third People’s Hospital, Hangzhou, Zhejiang Province, China

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Xiao-Wei Yang Department of Pediatrics, The First People’s Hospital of Wenling City, Wenling, Zhejiang Province, China

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Zhi-Lie Cao Department of Oncologic and Urologic Surgery, The 117th PLA Hospital, Wenzhou Medical University, Hangzhou, Zhejiang Province, China

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Xiu-Hua Yu Department of Oncologic and Urologic Surgery, The 117th PLA Hospital, Wenzhou Medical University, Hangzhou, Zhejiang Province, China

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Xu-Dong Fang Department of Oncologic and Urologic Surgery, The 117th PLA Hospital, Wenzhou Medical University, Hangzhou, Zhejiang Province, China

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Da-Hong Zhang Department of Urologic Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang Province, China

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Jian-Qiang Zhao Department of Head and Neck Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, China

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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.

Open access
Bekir Cakir Department of Endocrinology and Metabolism, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey

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F Neslihan Cuhaci Seyrek Department of Endocrinology and Metabolism, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey

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Oya Topaloglu Department of Endocrinology and Metabolism, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey

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Didem Ozdemir Department of Endocrinology and Metabolism, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey

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Ahmet Dirikoc Department of Endocrinology and Metabolism, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey

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Cevdet Aydin Department of Endocrinology and Metabolism, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey

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Sefika Burcak Polat Department of Endocrinology and Metabolism, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey

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Berna Evranos Ogmen Department of Endocrinology and Metabolism, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey

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Ali Abbas Tam Department of Endocrinology and Metabolism, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey

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Husniye Baser Department of Endocrinology and Metabolism, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey

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Aylin Kilic Yazgan Department of Pathology, Ankara Ataturk Education and Research Hospital, Ankara, Turkey

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Mehmet Kilic Department of General Surgery, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey

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Afra Alkan Department of Biostatistics, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey

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Reyhan Ersoy Department of Endocrinology and Metabolism, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey

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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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Elizaveta Mamedova Department of Neuroendocrinology and Bone Diseases, Endocrinology Research Center, Moscow, Russian Federation

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Natalya Mokrysheva Department of Parathyroid Diseases, Endocrinology Research Center, Moscow, Russian Federation

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Evgeny Vasilyev Department and Laboratory of Inherited Endocrine Disorders, Endocrinology Research Center, Moscow, Russian Federation

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Vasily Petrov Department and Laboratory of Inherited Endocrine Disorders, Endocrinology Research Center, Moscow, Russian Federation

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Ekaterina Pigarova Department of Neuroendocrinology and Bone Diseases, Endocrinology Research Center, Moscow, Russian Federation

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Sergey Kuznetsov Department of Surgery, Endocrinology Research Center, Moscow, Russian Federation

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Nikolay Kuznetsov Department of Surgery, Endocrinology Research Center, Moscow, Russian Federation

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Liudmila Rozhinskaya Department of Neuroendocrinology and Bone Diseases, Endocrinology Research Center, Moscow, Russian Federation

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Galina Melnichenko I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
Institute of Clinical Endocrinology, Endocrinology Research Center, Moscow, Russian Federation

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Ivan Dedov Endocrinology Research Center, Moscow, Russian Federation

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Anatoly Tiulpakov Department and Laboratory of Inherited Endocrine Disorders, 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.

Open access
Elena Pardi Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Stefano Mariotti Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Natalia S Pellegata Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Katiuscia Benfini Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Simona Borsari Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Federica Saponaro Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Liborio Torregrossa Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Antonello Cappai Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Chiara Satta Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Marco Mastinu Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Claudio Marcocci Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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Filomena Cetani Endocrine Unit 2, Endocrinology Unit, Institute of Pathology, Department of Surgical, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Via Paradisa 2, Pisa, Italy

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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.

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