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Lu Yang Department of Nuclear Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China

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Xingguo Jing Department of Nuclear Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China

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Hua Pang Department of Nuclear Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China

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Lili Guan Department of Nuclear Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China

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Mengdan Li Department of Nuclear Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China

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In this review, we discuss the definition, prevalence, and etiology of sporadic multiglandular disease (MGD), with an emphasis on its preoperative and intraoperative predictors. Primary hyperparathyroidism (PHPT) is the third-most common endocrine disorder, and multiglandular parathyroid disease (MGD) is a cause of PHPT. Hereditary MGD can be definitively diagnosed with detailed family history and genetic testing, whereas sporadic MGD presents a greater challenge in clinical practice, and parathyroidectomy for MGD is associated with a higher risk of surgical failure than single gland disease (SGD). Therefore, it is crucial to be able to predict the presence of sporadic MGD in a timely manner, either preoperatively or intraoperatively. Various predictive methods cannot accurately identify all cases of sporadic MGD, but they can greatly optimize the management of MGD diagnosis and treatment and optimize the cure rate. Future research will urge us to investigate more integrative predictive models as well as increase our understanding of MGD pathogenesis.

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Kate E Lines Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Headington, Oxford, UK

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Mahsa Javid Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Headington, Oxford, UK

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Anita A C Reed Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Headington, Oxford, UK

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Gerard V Walls Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Headington, 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 (OCDEM), Churchill Hospital, Headington, Oxford, UK

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Michelle Simon MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire, 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 (OCDEM), Churchill Hospital, Headington, 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 (OCDEM), Churchill Hospital, Headington, 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 (OCDEM), Churchill Hospital, Headington, Oxford, UK

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Paul J Newey Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Headington, Oxford, UK

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Ann-Marie Mallon MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire, 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 (OCDEM), Churchill Hospital, Headington, Oxford, UK

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Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder caused by MEN1 germline mutations, is characterised by parathyroid, pancreatic and pituitary tumours. MEN1 mutations also cause familial isolated primary hyperparathyroidism (FIHP), a milder condition causing hyperparathyroidism only. Identical mutations can cause either MEN1 or FIHP in different families, thereby implicating a role for genetic modifiers in altering phenotypic expression of tumours. We therefore investigated the effects of genetic background and potential for genetic modifiers on tumour development in adult Men1+/- mice, which develop tumours of the parathyroids, pancreatic islets, anterior pituitary, adrenal cortex and gonads, that had been backcrossed to generate C57BL/6 and 129S6/SvEv congenic strains. A total of 275 Men1+/- mice, aged 5–26 months were macroscopically studied, and this revealed that genetic background significantly influenced the development of pituitary, adrenal and ovarian tumours, which occurred in mice over 12 months of age and more frequently in C57BL/6 females, 129S6/SvEv males and 129S6/SvEv females, respectively. Moreover, pituitary and adrenal tumours developed earlier, in C57BL/6 males and 129S6/SvEv females, respectively, and pancreatic and testicular tumours developed earlier in 129S6/SvEv males. Furthermore, glucagon-positive staining pancreatic tumours occurred more frequently in 129S6/SvEv Men1+/- mice. Whole genome sequence analysis of 129S6/SvEv and C57BL/6 Men1+/- mice revealed >54,000 different variants in >300 genes. These included, Coq7, Dmpk, Ccne2, Kras, Wnt2b, Il3ra and Tnfrsf10a, and qRT-PCR analysis revealed that Kras was significantly higher in pituitaries of male 129S6/SvEv mice. Thus, our results demonstrate that Kras and other genes could represent possible genetic modifiers of Men1.

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Mojca Zerjav Tansek Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children’s Hospital, UMC Ljubljana, Ljubljana, Slovenia
University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia

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Ana Bertoncel University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia

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Brina Sebez University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia

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Janez Zibert Centre for Health Informatics and Statistics, Faculty of Health Sciences, University of Ljubljana, Ljubljana, Slovenia

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Urh Groselj Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children’s Hospital, UMC Ljubljana, Ljubljana, Slovenia
University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia

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Tadej Battelino Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children’s Hospital, UMC Ljubljana, Ljubljana, Slovenia
University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia

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Magdalena Avbelj Stefanija Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children’s Hospital, UMC Ljubljana, Ljubljana, Slovenia
University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia

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Despite recent improvements in the composition of the diet, lower mineral bone density and overweight tendencies are incoherently described in patients with phenylketonuria (PKU). The impact of dietary factors and plasma phenylalanine levels on growth, BMI, body composition, and bone mineral density was investigated in our cohort of patients with hyperphenylalaninemia (HPA) with or without dietary treatment. The anthropometric, metabolic, BMI and other nutritional indicators and bone mineral density were compared between the group of 96 treated patients with PKU (58 classic PKU (cPKU) and 38 patients with moderate-mild PKU defined as non-classic PKU (non-cPKU)) and the untreated group of 62 patients with benign HPA. Having compared the treated and untreated groups, there were normal outcomes and no statistically significant differences in BMI, body composition, and bone mineral density. Lower body height standard deviation scores were observed in the treated as compared to the untreated group (P < 0.001), but the difference was not significant when analyzing patients older than 18 years; however, cPKU adults were shorter compared to non-cPKU treated adults (P = 0.012). Interestingly, the whole-body fat was statistically higher in non-cPKU as compared to cPKU patients. In conclusion, the dietary treatment ensured adequate nutrition without significant consequences in BMI, body composition, and bone mineral density. A low protein diet may have delayed the growth in childhood, but the treated patients gained a normal final height. Mild untreated hyperphenylalaninemia characteristic for benign HPA had no negative physiological effect on bone mineral density.

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Lizhi Zhang Department of Endocrinology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Department of Endocrinology, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

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Jinwei He Department of Osteoporosis and Bone Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China

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Xiang Sun Shanghai Institute of Technology, Shanghai, China

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Dongyue Pang Department of Endocrinology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China

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Jingjing Hu Department of Endocrinology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China

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Bo Feng Department of Endocrinology, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

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We demonstrated previously that there is a correlation between glucagon-like peptide-1 (GLP-1) single-nucleotide polymorphism (SNP) and bone mineral density in postmenopausal women. Both GLP-1 and glucose-dependent insulinotropic peptide are incretins. The glucose-dependent insulinotropic peptide receptor (GIPR) SNP rs10423928 has been extensively studied. However, it is not clear whether GIPR gene mutations affect bone metabolism. The aim of this study was to investigate the association between rs10423928 and bone mineral density in postmenopausal women in Shanghai. rs10423928 was detected in 884 postmenopausal women in Shanghai, and the correlation between the GIPR SNP and bone mineral density was assessed. The dominant T/T genotype of rs10423928 was found to be related to the bone mineral density of the femoral neck (P = 0.035). Overall, our findings indicate that the dominant T/T genotype of rs10423928 in postmenopausal women is significantly associated with a higher bone mineral density and that the T/T genotype exerts a bone-protective effect.

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W N H Koek Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands

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N Campos-Obando Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands

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B C J van der Eerden Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands

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Y B de Rijke Department of Clinical Chemistry, Erasmus MC, University Medical Center, Rotterdam, the Netherlands

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M A Ikram Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands

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A G Uitterlinden Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands

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J P T M van Leeuwen Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands

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M C Zillikens Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands

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Background

Sex differences in calcium and phosphate have been observed. We aimed to assess a relation with age.

Methods

We used the laboratory values of serum calcium, phosphate and albumin from three different samples ( 2005, 2010 and 2014 years) using the hospital information system of Erasmus MC, Rotterdam. The samples were divided into three age groups: 1–17, 18–44 and ≥45 years. Sex differences in calcium and phosphate were analyzed using ANCOVA, adjusting for age and serum albumin. Furthermore, sex by age interactions were determined and we analyzed differences between age groups stratified by sex.

Results

In all three samples there was a significant sex × age interaction for serum calcium and phosphate, whose levels were significantly higher in women compared to men above 45 years. No sex differences in the younger age groups were found. In men, serum calcium and phosphate levels were highest in the youngest age group compared to age groups of 18–44 and ≥45 years. In women, serum calcium levels were significantly higher in the age group 1–17 and the age group ≥45 years compared to the 18–44 years age group. In women, serum phosphate was different between the three different age groups with highest level in the group 1–17 years and lowest in the group 18–44 years.

Conclusion

There are age- dependent sex differences in serum calcium and phosphate. Furthermore, we found differences in serum calcium and phosphate between different age groups. Underlying mechanisms for these age- and sex- differences are not yet fully elucidated.

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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
Martine Cohen-Solal Department of Skeletal Diseases, INSERM U1132 & Université de Paris, Hôpital Lariboisière, Paris, France

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Thomas Funck-Brentano Department of Skeletal Diseases, INSERM U1132 & Université de Paris, Hôpital Lariboisière, Paris, France

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Pablo Ureña Torres AURA Nord, Saint Ouen, France
Department of Renal Physiology, Necker Hospital, Université de Paris, Paris, France

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Mineral and bone diseases (MBD) are predominant in patients with chronic kidney disease (CKD) and lead to several bone manifestations, from pain to skeletal fractures. Cumulative traditional clinical risk factors, such as age and gender, in addition to those related to CKD, enhance the risk of comorbidity and mortality related to fractures. Despite great advances in understanding MBD in CKD, clinical and biological targets are lacking, which leads to under-management of fractures. Optimal PTH control results in a net improvement in defining the levels of bone remodeling. In addition, circulating biomarkers such as bone-specific alkaline phosphatase and cross-linked collagen type I peptide will also provide additional information about remodeling rate, bone mineralization and the evaluation of fracture risk. Imaging techniques identify patients at risk by measurement of bone mineral density by DEXA or by high peripheral QCT, which allow the discrimination of trabecular and cortical bone. Here, we have reviewed the literature related to epidemiology and the pathophysiological role of mineral and biochemical factors involved in CKD-MBD with a special focus on fracture risk. We also provide an algorithm that could be used for the management of bone diseases and to guide treatment decisions. Finally, the combined expertise of clinicians from various disciplines is crucial for the best prevention of fractures.

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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.

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