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E M Winter Leiden University Medical Center, Department of Internal Medicine, Division of Endocrinology, Center for Bone Quality, Leiden, the Netherlands

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A Ireland Musculoskeletal Science and Sports Medicine Research Centre, Department of Life Sciences, Manchester Metropolitan University, Manchester, United Kingdom

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N C Butterfield Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London, Commonwealth Building, DuCane Road, London, United Kingdom

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M Haffner-Luntzer Institute of Orthopaedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany

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M-N Horcajada Nestlé Research, Department of Musculoskeletal Health, Innovation EPFL Park, Lausanne, Switzerland.

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A G Veldhuis-Vlug Leiden University Medical Center, Department of Internal Medicine, Division of Endocrinology, Center for Bone Quality, Leiden, the Netherlands
Jan van Goyen Medical Center, Department of Internal Medicine, Amsterdam, the Netherlands

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L Oei Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

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G Colaianni Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy

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N Bonnet Nestlé Research, Department of Musculoskeletal Health, Innovation EPFL Park, Lausanne, Switzerland.

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In this review we discuss skeletal adaptations to the demanding situation of pregnancy and lactation. Calcium demands are increased during pregnancy and lactation, and this is effectuated by a complex series of hormonal changes. The changes in bone structure at the tissue and whole bone level observed during pregnancy and lactation appear to largely recover over time. The magnitude of the changes observed during lactation may relate to the volume and duration of breastfeeding and return to regular menses. Studies examining long-term consequences of pregnancy and lactation suggest that there are small, site-specific benefits to bone density and that bone geometry may also be affected. Pregnancy- and lactation-induced osteoporosis (PLO) is a rare disease for which the pathophysiological mechanism is as yet incompletely known; here, we discuss and speculate on the possible roles of genetics, oxytocin, sympathetic tone and bone marrow fat. Finally, we discuss fracture healing during pregnancy and lactation and the effects of estrogen on this process.

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Katherine U Gaynor Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK

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Irina V Grigorieva Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK

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Samantha M Mirczuk Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK

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Sian E Piret Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK

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Kreepa G Kooblall Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK

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Mark Stevenson Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK

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Karine Rizzoti The Francis Crick Institute, London, UK

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Michael R Bowl Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK

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M Andrew Nesbit Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK

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Paul T Christie Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK

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William D Fraser Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK

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Tertius Hough MRC Mammalian Genetics Unit, MRC Harwell Institute, Harwell Science and Innovation Campus, Oxfordshire, UK

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Michael P Whyte Washington University in St Louis School of Medicine, Center for Metabolic Bone Disease and Molecular Research, St Louis, Missouri, USA

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Robin Lovell-Badge The Francis Crick Institute, London, UK

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Rajesh V Thakker Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK

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Hypoparathyroidism is genetically heterogeneous and characterized by low plasma calcium and parathyroid hormone (PTH) concentrations. X-linked hypoparathyroidism (XLHPT) in two American families is associated with interstitial deletion-insertions involving deletions of chromosome Xq27.1 downstream of SOX3 and insertions of predominantly non-coding DNA from chromosome 2p25.3. These could result in loss, gain, or movement of regulatory elements, which include ultraconserved element uc482, which could alter SOX3 expression. To investigate this, we analysed SOX3 expression in EBV-transformed lymphoblastoid cells from three affected males, three unaffected males, and four carrier females from one XLHPT family. SOX3 expression was similar in all individuals, indicating that the spatiotemporal effect of the interstitial deletion-insertion on SOX3 expression postulated to occur in developing parathyroids did not manifest in lymphoblastoids. Expression of SNTG2, which is duplicated and inserted into the X chromosome, and ATP11C, which is moved telomerically, were also similarly expressed in all individuals. Investigation of male hemizygous (Sox3 −/Y and uc482 −/Y) and female heterozygous (Sox3 +/ and uc482 +/ ) knockout mice, together with wild-type littermates (male Sox3 +/Y and uc482 +/Y, and female Sox3 +/+ and uc482 +/+), revealed Sox3 −/Y, Sox3 +/ , uc482 /Y, and uc482 +/ mice to have normal plasma biochemistry, compared to their respective wild-type littermates. When challenged with a low calcium diet, all mice had hypocalcaemia, and elevated plasma PTH concentrations and alkaline phosphatase activities, and Sox3 −/Y, Sox3 +/ , uc482 −/Y, and uc482 +/ mice had similar plasma biochemistry, compared to wild-type littermates. Thus, these results indicate that absence of Sox3 or uc482 does not cause hypoparathyroidism and that XLHPT likely reflects a more complex mechanism.

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Qian Wang Department of Thyroid and Neck Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China

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Jiacheng Wang Department of Thyroid and Neck Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China

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Yunhui Xin Department of Thyroid and Neck Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China

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Ziyang He Department of Thyroid and Neck Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China

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Xiang Zhou Department of Pathology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China

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Xing Liu Department of Thyroid and Neck Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China

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Teng Zhao Department of Thyroid and Neck Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China

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Lihan He Department of Thyroid and Neck Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China

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Hong Shen Department of Thyroid and Neck Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China

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Mulan Jin Department of Pathology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China

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Bojun Wei Department of Thyroid and Neck Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China

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Background

Parathyroid carcinoma (PC), often misdiagnosed as a parathyroid adenoma (PA), is prone to local relapse due to the initial surgery being restricted to parathyroid lesions instead of en bloc resection of parathyroid lesions with negative incision margins. However, it is very challenging to distinguish PC from PA preoperatively; hence, this study investigated an effective biomarker for increasing accuracy in PC diagnosis.

Method

First, the differentially expressed circular RNAs between three PC tissues and three PA tissues were screened by high-throughput circular RNA sequencing, and the expression of hsa_circ_0005729 was verified by qRT-PCR in 14 patients with PC and 40 patients with PA. Secondly, the receiver operating characteristic curve and the area under the curve (AUC) were used to analyze the diagnostic efficiency of hsa_circ_0005729 in PC by combining with laboratory data. Thirdly, RNF138mRNA, the corresponding linear transcript of hsa_circ_0005729, was measured, and the relationship between hsa_circ_0005729 and RNF138 mRNA was analyzed in patients with PA and patients with PC.

Results

Hsa_circ_0005729 expression was significantly higher in patients with PC than in patients with PA. Serum calcium (P  = 0.045), alkaline phosphatase (ALP) (P  = 0.048), and creatinine levels (P  = 0.036) were significantly higher in patients with PC than in patients with PA. The AUC increased to 0.86 when hsa_circ_0005729 combined with serum calcium, creatinine, and ALP. In addition, hsa_circ_0005729 was positively correlated with RNF138 mRNA in patients with PA but not in patients with PC.

Conclusion

The novel circular RNA hsa_circ_0005729 was found to have a higher expression in patients with PC, indicating its usefulness for distinguishing PC from PA.

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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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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.

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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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Luchuan Li Department of Thyroid Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China

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Baoyuan Li Department of Thyroid Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China

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Bin Lv Department of Thyroid Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China

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Weili Liang Department of Thyroid Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China

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Binbin Zhang Department of Thyroid Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China

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Qingdong Zeng Department of Thyroid Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China

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Andrew G Turner Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia

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Lei Sheng Department of Thyroid Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China

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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.

Open access
Louise Vølund Larsen Department of ORL Head & Neck Surgery and Audiology, Odense University Hospital, Odense, Denmark

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Delphine Mirebeau-Prunier Laboratoire de Biochimie et Biologie Moléculaire, CHU Angers, Université d’Angers, UMR CNRS 6015, INSERM U1083, MITOVASC, Angers, France

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Tsuneo Imai Department of Breast & Endocrine Surgery, National Hospital Organization, Higashinagoya National Hospital

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Cristina Alvarez-Escola Endocrinology and Nutrition Department, University Hospital ‘La Paz’, Madrid, Spain

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Kornelia Hasse-Lazar Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland

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Simona Censi Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy

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Luciana A Castroneves Department of Endocrinology, Endocrine Oncology Unit, Instituto do Cancer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Akihiro Sakurai Department of Medical Genetics and Genomics, Sapporo Medical University School of Medicine, Sapporo, Japan

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Minoru Kihara Department of Surgery, Kuma Hospital, Kobe, Hyogo, Japan

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Kiyomi Horiuchi Department of Breast and Endocrine Surgery, Tokyo Women’s Medical University, Tokyo, Japan

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Véronique Dorine Barbu AP-HP, Sorbonne Université, Laboratoire Commun de Biologie et Génétique Moléculaires, Hôpital St Antoine & INSERM CRSA, Paris, France
Réseau TenGen, Marseille, France

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Francoise Borson-Chazot Réseau TenGen, Marseille, France
Fédération d’Endocrinologie, Hospices Civils de Lyon, Université Lyon 1, France

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Anne-Paule Gimenez-Roqueplo Réseau TenGen, Marseille, France
Service de Génétique, AP-HP, Hôpital européen Georges Pompidou, Paris, France
Université de Paris, PARCC, INSERM, Paris, France

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Pascal Pigny Réseau TenGen, Marseille, France
Laboratoire de Biochimie et Oncologie Moléculaire, CHU Lille, Lille, France

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Stephane Pinson Réseau TenGen, Marseille, France
Laboratoire de Génétique Moléculaire, CHU Lyon, Lyon, France

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Nelson Wohllk Endocrine Section, Hospital del Salvador, Santiago de Chile, Department of Medicine, University of Chile, Santiago, Chile

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Charis Eng Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA

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Berna Imge Aydogan Department of Endocrinology And Metabolic Diseases, Ankara University School of Medicine, Ankara, Turkey

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Dhananjaya Saranath Department of Research Studies & Additional Projects, Cancer Patients Aid Association, Dr. Vithaldas Parmar Research & Medical Centre, Worli, Mumbai, India

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Sarka Dvorakova Department of Molecular Endocrinology, Institute of Endocrinology, Prague, Czech Republic

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Frederic Castinetti Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Marseille, France
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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Attila Patocs HAS-SE Momentum Hereditary Endocrine Tumors Research Group, Semmelweis University, Budapest, Hungary

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Damijan Bergant Department of Surgical Oncology, Institute of Oncology, Ljubljana, Slovenia

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Thera P Links Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands

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Mariola Peczkowska Department of Hypertension, Institute of Cardiology, Warsaw, Poland

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Ana O Hoff Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands

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Caterina Mian Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy

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Trisha Dwight Cancer Genetics, Kolling Institute, Royal North Shore Hospital and University of Sydney, Sydney, New South Wales, Australia

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Barbara Jarzab Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland

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Hartmut P H Neumann Section for Preventive Medicine, Medical Center-University of Freiburg, Faculty of Medicine, Albert Ludwigs-University of Freiburg, Freiburg, Germany

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Mercedes Robledo Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

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Shinya Uchino Department of Endocrine Surgery, Noguchi Thyroid Clinic and Hospital Foundation, Beppu, Oita, Japan

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Anne Barlier Réseau TenGen, Marseille, France
Aix Marseille Univ, APHM, INSERM, MMG, Laboratory of Molecular Biology, Hospital La Conception, Marseille, France

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Christian Godballe Department of ORL Head & Neck Surgery and Audiology, Odense University Hospital, Odense, Denmark

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Jes Sloth Mathiesen Department of ORL Head & Neck Surgery and Audiology, Odense University Hospital, Odense, Denmark
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.

Open access
Marília D’Elboux Guimarães Brescia Endocrine Genetics Unit (LIM-25), Endocrinology Division, University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Hospital das Clinicas (HCFMUSP), São Paulo, São Paulo, Brazil
Parathyroid Unit – LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Division of Head and Neck Surgery, Department of Surgery, Hospital das Clinicas (HCFMUSP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil

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Karine Candido Rodrigues Endocrine Genetics Unit (LIM-25), Endocrinology Division, University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Hospital das Clinicas (HCFMUSP), São Paulo, São Paulo, Brazil
Endocrine Oncology Division, Institute of Cancer of the State of São Paulo (ICESP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, São Paulo, Brazil

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André Fernandes d’Alessandro Parathyroid Unit – LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Division of Head and Neck Surgery, Department of Surgery, Hospital das Clinicas (HCFMUSP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil

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Wellington Alves Filho Department of Surgery, Walter Cantidio University Hospital, Federal University of Ceara School of Medicine (FAMED-UFC), Fortaleza, Brazil

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Willemijn Y van der Plas Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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Schelto Kruijff Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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Sergio Samir Arap Parathyroid Unit – LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Division of Head and Neck Surgery, Department of Surgery, Hospital das Clinicas (HCFMUSP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil

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Sergio Pereira de Almeida Toledo Endocrine Genetics Unit (LIM-25), Endocrinology Division, University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Hospital das Clinicas (HCFMUSP), São Paulo, São Paulo, Brazil

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Fábio Luiz de Menezes Montenegro Parathyroid Unit – LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Division of Head and Neck Surgery, Department of Surgery, Hospital das Clinicas (HCFMUSP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil

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Delmar Muniz Lourenço Jr Endocrine Genetics Unit (LIM-25), Endocrinology Division, University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Hospital das Clinicas (HCFMUSP), São Paulo, São Paulo, Brazil
Endocrine Oncology Division, Institute of Cancer of the State of São Paulo (ICESP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, São Paulo, Brazil

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Background

Potential influences of parathyroidectomy (PTx) on the quality of life (QoL) in multiple endocrine neoplasia type 1-related primary hyperparathyroidism (HPT/MEN1) are unknown.

Method

Short Form 36 Health Survey Questionnaire was prospectively applied to 30 HPT/MEN1 patients submitted to PTx (20, subtotal; 10, total with autograft) before, 6 and 12 months after surgery. Parameters that were analyzed included QoL, age, HPT-related symptoms, general pain, comorbidities, biochemical/hormonal response, PTx type and parathyroid volume.

Results

Asymptomatic patients were younger (30 vs 38 years; P = 0.04) and presented higher QoL scores than symptomatic ones: Physical Component Summary score (PCS) 92.5 vs 61.2, P = 0.0051; Mental Component Summary score (MCS) 82.0 vs 56.0, P = 0.04. In both groups, QoL remained stable 1 year after PTx, independently of the number of comorbidities. Preoperative general pain was negatively correlated with PCS (r = −0.60, P = 0.0004) and MCS (r = −0.57, P = 0.0009). Also, moderate/intense pain was progressively (6/12 months) more frequent in cases developing hypoparathyroidism. The PTx type and hypoparathyroidism did not affect the QoL at 12 months although remnant parathyroid tissue volume did have a positive correlation (P = 0.0490; r = 0.3625) to PCS 12 months after surgery. Patients with one to two comorbidities had as pre-PTx PCS (P = 0.0015) as 12 months and post-PTx PCS (P = 0.0031) and MCS (P = 0.0365) better than patients with three to four comorbidities.

Conclusion

A variable QoL profile was underscored in HPT/MEN1 reflecting multiple factors associated with this complex disorder as comorbidities, advanced age at PTx and presence of preoperative symptoms or of general pain perception. Our data encourage the early indication of PTx in HPT/MEN1 by providing known metabolic benefits to target organs and avoiding potential negative impact on QoL.

Open access