Publications by authors named "Xiaoping Xing"

141 Publications

Bone Microarchitecture in Obese Postmenopausal Chinese Women: The Chinese Vertebral Osteoporosis Study (ChiVOS).

Front Endocrinol (Lausanne) 2022 5;13:891413. Epub 2022 Jul 5.

Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.

Background: Obesity is associated with improved bone mass and microarchitecture in Caucasian individuals, but evidence in obese Asian individuals is lacking.

Objective: To analyze the areal bone mineral density (aBMD) and bone microarchitecture in normal-weight, overweight, and obese postmenopausal Chinese women.

Methods: A total of 243 postmenopausal women from the Chinese Vertebral Osteoporosis Study (ChiVOS) were included and were divided into three groups (OB, obese group; OW, overweight group; NW, normal weight group) by BMI level. aBMD, trabecular bone score (TBS), and appendicular lean mass (ALM) were measured by dual-energy X-ray absorptiometry (DXA). Bone microarchitecture was measured by HR-pQCT at the distal radius and tibia. X-ray was performed to confirm vertebral fractures (VFs). Multiple linear regression was used to evaluate the correlations between bone parameters and ALM after adjusting for confounding variables.

Results: The prevalence of VFs and clinical fractures were similar among the groups. Participants in the OB group showed a lower level of osteocalcin with comparable levels of other bone turnover markers (BTMs). The aBMD at several skeletal sites was higher in the OB group than in the NW group after adjusting for age (<0.01 for all comparisons). At the radius, the OB group had a higher Ct.Ar, Tb.vBMD, Tb.BV/TV, Tb.N, Tb.Th, and Ct.Th than the NW group after adjusting for covariates (<0.05 for all). Differences of a similar magnitude were found at the distal tibia. There was a trend of decreasing trend in Tb.Sp, Tb.1/N/SD, and Ct.Po among groups at both sites. However, the bone microarchitecture did not differ between participants with severe obesity (BMI≥35.0kg/m) and those with 30.0≤BMI<35 kg/m. Multiple linear regression revealed that the associations between ALM and most of the bone microarchitecture parameters at both sites were much stronger than the association between body weight and bone parameters.

Conclusion: We have observed significant improvements in aBMD, bone geometry, and bone microarchitecture in obese postmenopausal Chinese women. Except for a lower level of osteocalcin in the OB group, no significant differences in BTMs were found among the groups. Compared with body weight, ALM may explain greater variance in the improvement of bone microarchitecture parameters.
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http://dx.doi.org/10.3389/fendo.2022.891413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9294215PMC
July 2022

A Novel Synonymous Variant of PHEX in a Patient with X-Linked Hypophosphatemia.

Calcif Tissue Int 2022 Jul 14. Epub 2022 Jul 14.

Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, People's Republic of China.

X-linked dominant hypophosphatemia (XLH), the most common form of hereditary hypophosphatemic rickets/osteomalacia, is caused by loss-of-function phosphate-regulating endopeptidase homolog X-linked gene (PHEX) variants. However, synonymous PHEX variants are rare in XLH. We report a 7-year-old boy with hypophosphatemia, short stature, and lower limb deformity. Whole-exome sequencing, reverse transcription-polymerase chain reaction, and Sanger sequencing were performed to identify the pathogenicity of the variant. A novel synonymous PHEX variant (NM_000444.4:c.1530 C>T, p.Arg510Arg) was detected in the proband. Further analysis revealed a 58-bp deletion at the 5' site of exon 14 during splicing. This study extends the genetic spectrum of XLH and confirms the rarity and significance of synonymous PHEX variants.
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http://dx.doi.org/10.1007/s00223-022-01003-wDOI Listing
July 2022

Bone Volumetric Density, Microarchitecture, and Estimated Bone Strength in Tumor-Induced Rickets/Osteomalacia X-linked Hypophosphatemia in Chinese Adolescents.

Front Endocrinol (Lausanne) 2022 13;13:883981. Epub 2022 Jun 13.

Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China.

Tumor-induced rickets/osteomalacia (TIR/O) severely impairs bone microarchitecture and bone strength. However, no study has described the microarchitectural quality of bone in adolescent patients with TIR/O. TIR/O affects bone quality more severely than the inherited causes of hypophosphatemia, the most common form of which is X-linked hypophosphatemia (XLH). Nevertheless, differences of the microarchitectural quality of the bone between TIR/O and XLH have never been clarified. Therefore, in this study, we used high-resolution peripheral quantitative computed tomography to assess bone microarchitecture in five Chinese adolescent TIR/O patients, and these were compared with 15 age- and gender-matched XLH patients as well as 15 age- and gender-matched healthy controls. Compared with the healthy controls, the TIR/O patients presented with significantly lower volumetric bone mineral densities (vBMDs), severely affected bone microarchitecture, and profoundly weaker bone strength. The distal tibia was more severely affected than the distal radius. Compared with the XLH patients, the TIR/O patients showed deteriorated bone quality notably at the distal tibia and in the cancellous compartment, reflected by 45.9% lower trabecular vBMD ( = 0.029), 40.2% lower trabecular fraction ( = 0.020), 40.6% weaker stiffness ( = 0.058), and 42.7% weaker failure load ( = 0.039) at the distal tibia. The correlation analysis showed that a higher level of serum FGF23 and a lower level of serum phosphate were associated with a poorer bone microarchitecture and a weaker estimated bone strength in the hypophosphatemic patients of our study. In conclusion, our study demonstrated significantly lower vBMDs, severely impaired bone microarchitecture, and profoundly weaker bone strength in Chinese adolescent patients with TIR/O, notably at the distal tibia, compared with the same parameters in age- and sex-matched healthy controls and XLH patients, which was possibly caused by excessive FGF23 production and secretion, chronically severe hypophosphatemia, and weak mechanical stimulus at the lower extremities. These findings further our understanding of the impact of different kinds of hypophosphatemic rickets/osteomalacia on bone quality.
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http://dx.doi.org/10.3389/fendo.2022.883981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9234144PMC
July 2022

Na-Cl Co-transporter (NCC) gene inactivation is associated with improved bone microstructure.

Osteoporos Int 2022 Jun 29. Epub 2022 Jun 29.

Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Shuaifuyuan No.1, Wangfujing Street, Dongcheng District, Beijing, 100730, China.

Gitelman syndrome (GS) is the disease model of the inactivation of thiazide-sensitive sodium chloride cotransporter (NCC), which is believed to benefit bone mass and reduce fracture risk. In this study, we found that GS patients have superior bone microarchitecture, which is associated with the disease status. Several decreased bone parameters with aging in healthy controls were reversed in GS patients to a certain extent.

Purpose: To evaluate the impact of the inactivation of NCC on bone turnover and microarchitecture in Gitelman syndrome patients.

Methods: A cross-sectional study was conducted in 45 GS patients (25 males and 20 females). Serum procollagen type 1 N-terminal propeptide (P1NP), β-carboxy-terminal crosslinked telopeptide of type 1 collagen (β-CTX), and osteocalcin were measured. High-resolution peripheral quantitative computed tomography (HR-pQCT) was conducted to evaluate bone microarchitecture in GS patients and age- and sex-matched healthy controls. Areal bone mineral density (aBMD) was measured by dual-energy X-ray absorptiometry (DXA) simultaneously.

Results: GS patients had a relatively lower level of β-CTX. aBMD at several skeletal sites was improved in GS patients. HR-pQCT assessment revealed that GS patients had slightly thinner but significantly more compact trabecular bone (increased trabecular number and decreased thickness), notably decreased cortical porosity, and increased volume BMD (vBMD) at both the radius and tibia compared with controls. The disease severity, represented as the relationship with the minimum level of magnesium during the course and standard base excess, was associated with bone microarchitecture parameters after adjusting for age, sex, and BMI. The decreased vBMD and Tb.BV/TV, and increased Tb.Sp and Ct.Po with aging, were reversed in GS patients to a certain extent.

Conclusion: GS patients have superior bone microarchitecture, which suggests that the inactivation of NCC might be beneficial for avoiding osteoporosis.
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http://dx.doi.org/10.1007/s00198-022-06471-2DOI Listing
June 2022

Relationship of pathogenic mutations and responses to zoledronic acid in a cohort of osteogenesis imperfecta children.

J Clin Endocrinol Metab 2022 Jun 21. Epub 2022 Jun 21.

Department of Endocrinology, Key Laboratory of Endocrinology of National Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.

Context: Osteogenesis imperfecta (OI) is a rare, heterogeneous genetic disorder characterized by bone fragility and recurrent fractures. Bisphosphonates (BPs) are the most commonly used medications for OI, but their efficacy has great variability.

Objective: We investigate the relationship of pathogenic gene mutations and responses to zoledronic acid (ZOL) in a large cohort of OI children.

Methods: Children with OI were included who received ZOL treatment and followed up for at least one year. Bone mineral density (BMD), serum levels of β-isomerized carboxy-telopeptide of type I collagen (β-CTX, bone resorption marker) were measured at baseline and during follow-up. Causative mutations of OI were identified using next-generation sequencing and Sanger sequencing.

Results: 201 OI children were included who initiated ZOL treatment at a median age of 5 years, with mutations identified in 11 genes. After 3 years of treatment, the increase of femoral neck BMD Z-score in OI patients with autosomal dominant inheritance (AD) was greater than that in patients with autosomal recessive or X-linked inheritance (non-AD) (4.5±2.9 vs. 2.0±1.0, P<0.001). Collagen structural defects were negatively correlated with the increase of femoral neck BMD Z-score. Patients with collagen structural defects had higher incidence of new fracture (35.1% vs. 18.4%, Relative risk 0.52, P=0.044) and less decline in β-CTX level than those with collagen quantitative reduction. Increase in lumbar spine BMD as well as change in height Z-score was not associated with the genotype of OI children.

Conclusion: OI patients with non-AD inheritance or with pathogenic mutations leading to collagen structural defects may have relatively poor responses to ZOL treatment, which is possibly associated with their more severe phenotypes. New therapeutic agents are worth developing in these patients.
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http://dx.doi.org/10.1210/clinem/dgac366DOI Listing
June 2022

Oral fat tolerance testing identifies abnormal pancreatic β-cell function and insulin resistance in individuals with normal glucose tolerance.

J Diabetes Investig 2022 Jun 9. Epub 2022 Jun 9.

Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, China.

Aims/introduction: Insulin sensitivity and β-cell function are affected by lipid metabolism disorders, even before the onset of type 2 diabetes. People are in the postprandial state most of the time. Therefore, identifying postprandial hyperlipemia is important. This study aimed to assess patients with abnormalities in lipid metabolism, but with normal glucose tolerance, using oral fat tolerance testing (OFTT) to identify defects in insulin sensitivity and β-cell function.

Materials And Methods: We included 248 volunteers with normal glucose tolerance who underwent OFTT. They were divided into three groups in accordance with their fasting and 4-h postprandial triglyceride (TG) concentrations. Their lipid concentrations during OFTT were compared. The disposition index (DI) was applied to estimate β-cell function, and the Matsuda insulin sensitivity index (ISI ) was used to assess insulin sensitivity. We used multiple linear regression analysis to estimate the relationships of fasting and postprandial TG concentrations with β-cell function and insulin sensitivity .

Results: The changes in TG concentrations during OFTT were more marked than those in low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol or total cholesterol concentrations. As lipid metabolism deteriorated, the ISI and the DI gradually decreased. Multiple linear regression analysis showed that fasting and 4-h postprandial TG concentrations affected LnISI and LnDI.

Conclusions: In individuals with normal glucose tolerance, β-cell function and insulin sensitivity gradually decrease with a deterioration in the lipid profile. Not only fasting TG, but also postprandial TG concentrations are independent risk factors for impaired β-cell function and insulin resistance.
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http://dx.doi.org/10.1111/jdi.13867DOI Listing
June 2022

[Identification of c.196C>T nonsense RUNX2 variant in a Chinese patient with cleidocranial dysplasia].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2022 May;39(5):526-529

Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.

Objective: To detect the genetic variant of a child with cleidocranial dysplasia (CCD) and to find out the causation of the illness.

Methods: Gene variant was identified by the second generation targeted sequencing and Sanger sequencing.

Results: The gene sequencing revealed that the RUNX2 gene had c.196C>T(p.Glu66*) nonsense variant, which was predicted to be a pathogenic variant according to the ACMG guidelines(PVS1+PS2).

Conclusion: The variant of c.196C > T in the RUNX2 gene may be the cause of the child with CCD, and the novel variant enriches the RUNX2 gene variant spectrum.
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http://dx.doi.org/10.3760/cma.j.cn511374-20210119-00055DOI Listing
May 2022

Bone microstructure evaluated by TBS and HR-pQCT in Chinese adults with X-linked hypophosphatemia.

Bone 2022 07 18;160:116423. Epub 2022 Apr 18.

Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China. Electronic address:

X-linked hypophosphatemia (XLH) is the most common form of heritable hypophosphatemic rickets. Although generalized mineralization defects have been observed, elevated areal bone mineral density (aBMD) in the lumbar spine measured by dual-energy X-ray absorptiometry (DXA) has also been found in XLH. In contrast, high-resolution peripheral quantitative computed tomography (HR-pQCT) revealed lower volumetric BMD (vBMD) and damaged bone microstructure in the peripheral bone in XLH. Trabecular bone score (TBS), which can assess the trabecular microstructure in the lumbar spine, has not been explored in XLH. This study aimed to explore TBS and its correlations with biochemical indices and HR-pQCT parameters in adult XLH patients. A total of 66 patients with XLH (26 men and 40 women) aged 29.6 ± 9.6 years and 66 age- and sex-matched healthy controls were included. Z score of lumbar spine aBMD was relatively high [2.0 (0.6, 3.7)], with normal TBS (1.475 ± 0.129) in the XLH patients. HR-pQCT revealed larger total and trabecular area in the peripheral bone in the XLH group compared with the control group. In addition, lower trabecular and cortical vBMD, lower trabecular number with greater separation, and lower bone strength at both the radius and tibia were found in the XLH group compared with the control group. Smaller cortical area, lower thickness and higher porosity in the XLH group compared with controls were only found at the radius. TBS was not associated with any biochemical indices, while better HR-pQCT parameters correlated with higher serum phosphate and lower ALP levels. TBS was positively related with aBMD but not HR-pQCT parameters. In conclusion, adult patients with XLH had high bone mass and normal TBS in the lumbar spine but compromised microarchitecture and bone strength in the peripheral bone. This finding indicated a site-specific effect of the disease on the skeleton in the XLH patients.
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http://dx.doi.org/10.1016/j.bone.2022.116423DOI Listing
July 2022

Head-to-Head Comparison of Ga-DOTA-TATE and Ga-DOTA-JR11 PET/CT in Patients With Tumor-Induced Osteomalacia: A Prospective Study.

Front Oncol 2022 24;12:811209. Epub 2022 Feb 24.

Department of Nuclear Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: The purpose of this study is to compare the sensitivity of Ga-DOTA-JR11 and Ga-DOTA-TATE PET/CT for detecting the responsible tumor of tumor-induced osteomalacia (TIO) and investigate if Ga-DOTA-JR11 PET/CT can identify the culprit tumor of TIO in multiple suspicious lesions in Ga-DOTA-TATE PET/CT.

Methods: A total of 19 patients with suspected TIO were prospectively recruited in this study. Each patient underwent whole-body PET/CT scan 40-60 min postinjection using Ga-DOTA-TATE and Ga-DOTA-JR11 on the same PET/CT, respectively in sequence, and on consecutive days. The diagnosis of TIO was confirmed by the combination of the postsurgical pathological results of the tumor and clinical information.

Results: Among the 19 patients with TIO who were included in this study, culprit tumors from all patients were confirmed pathologically. Ga-DOTA-TATE PET/CT positively identified the causative tumor in 18/19 patients, whereas Ga-DOTA-JR11 PET/CT was positive in 11/19 patients (94.7% vs. 57.9%, respectively; < 0.05). Ga-DOTA-TATE PET/CT demonstrated more than one increased focal activity in 7 patients for a total of 16 lesions (3 lesions each in 2 patients and 2 lesions each in the rest 5 patients). However, seven of these 16 lesions showed concordant results on Ga-DOTA-JR11 PET/CT by demonstrating increased activity (one lesion in each of the 7 patients). The surgical specimens of the lesions in these 7 patients confirmed the phosphaturic mesenchymal tumor. A total of 11 culprit tumors were positive in both Ga-DOTA-TATE and Ga-DOTA-JR11 PET/CT. The SUVmax of 11 culprit tumors was significantly higher on Ga-DOTA-TATE PET/CT compared with that on Ga-DOTA-JR11 PET/CT (17.8 ± 12.5 vs. 6.8 ± 6.2; < 0.05).

Conclusions: Ga-DOTA-TATE PET/CT is more sensitive to Ga-DOTA-JR11 PET/CT in the detection of the culprit tumor of TIO. However, Ga-DOTA-JR11 PET/CT might be helpful to identify the tumor in multiple suspicious lesions in Ga-DOTA-TATE PET/CT.

Clinical Trial Registration: clinicaltrials.gov, identifier NCT04689893.
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http://dx.doi.org/10.3389/fonc.2022.811209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8913035PMC
February 2022

Identification of the Chinese Population That Can Benefit Most From Postprandial Lipid Testing: Validation of the Use of Oral Fat Tolerance Testing in Clinical Practice.

Front Endocrinol (Lausanne) 2022 18;13:831435. Epub 2022 Feb 18.

Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.

Background: Dyslipidemia has become increasingly prevalent in recent decades. Blood lipid concentrations are significantly influenced by diet; however, postprandial triglyceride concentration (PTG) is not often measured. PTG can reflect the risks of diabetes and cardiovascular disease, but not all individuals would benefit from PTG testing.

Objective: The aim of the present study was to determine the PTG response in a Chinese cohort and identify who would benefit from diagnostic PTG measurement.

Methods: A total of 400 Chinese adults were enrolled and underwent oral fat tolerance test (OFTT), which was well tolerated. The participants were assigned to groups according to their fasting triglyceride concentration to evaluate the usefulness of PTG testing. A PTG concentration > 2.5 mmol/L was defined as high (HPTG).

Results: Of the 400 participants, 78.9% showed an undesirable PTG response. Those with FTG ≥1.0 mmol/L had a delayed PTG peak and higher peak values. Seventy-five percent of those with 1.0 mmol/L ≤FTG <1.7 mmol/L had HPTG, of whom 18.6% had impaired glucose tolerance.

Conclusions: The present data confirm the previously reported predictive value of PTG testing. Moreover, the findings indicate that Chinese people with FTGs of 1.0 -1.7 mmol/L may benefit most from the identification of postprandial hyperlipidemia through OFTT because more than half of them have occult HPTG, which may require treatment. Thus, the detection of HPTG using an OFTT represents a useful means of identifying dyslipidemia and abnormal glucose metabolism early.

Clinical Trial Registration: [http://www.chictr.org.cn/index.aspx], identifier ChiCTR1800019514.
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http://dx.doi.org/10.3389/fendo.2022.831435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8894673PMC
April 2022

25-hydroxyvitamin D levels are inversely related to metabolic syndrome risk profile in northern Chinese subjects without vitamin D supplementation.

Diabetol Metab Syndr 2022 Jan 29;14(1):23. Epub 2022 Jan 29.

Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: The comparatively low 25 hydroxyvitamin D [25(OH)D] levels have been reported in patients with metabolic syndrome (MetS). Herein we investigated the cross-sectional and longitudinal relationships between serum 25(OH)D levels and MetS risk profile in northern middle-aged Chinese subjects without vitamin D supplementation.

Methods: A cohort of 211 participants including 151 MetS patients and 60 controls at 20-69 years of age were enrolled from suburban Beijing, China. The recruited MetS patients were subjected to diet and exercise counselling for 1-year. All subjects at baseline and MetS patients after intervention underwent clinical evaluations.

Results: Serum 25(OH)D levels were significantly decreased in MetS patients. 25(OH)D levels were inversely related to MetS score, fasting blood glucose (FBG) and triglyceride-glucose index (TyG) after adjusting for cofounders (all P < 0.05). Participants in the lowest tertile of 25(OH)D levels had increased odds for MetS (P = 0.045), elevated FBG (P = 0.004) in all subjects, and one MetS score gain in MetS patients (P = 0.005). Longitudinally, the metabolic statuses as well as 25(OH)D levels of MetS patients were significantly improved (all P < 0.05), and the increase of 25(OH)D levels were inversely related to MetS scores, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), FBG, and TyG, while positively related to high-density lipoprotein cholesterol (HDL-C) after adjusting for confounders.

Conclusions: 25(OH)D levels were significantly decreased in MetS patients, and it was negatively associated with metabolic dysfunctions at baseline and 1-year after. Metabolic aberrations of MetS patients were significantly ameliorated with 1-year follow-up counselling accompanying by notably elevated 25(OH)D levels.
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http://dx.doi.org/10.1186/s13098-022-00793-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8800320PMC
January 2022

Transcriptome Analysis and Functional Validation Identify a Putative bZIP Transcription Factor, Fpkapc, that Regulates Development, Stress Responses, and Virulence in .

Phytopathology 2022 Jun 29;112(6):1299-1309. Epub 2022 Apr 29.

College of Plant Protection, Henan Agricultural University, Zhengzhou 450000, China.

is a soilborne, hemibiotrophic phytopathogenic fungus that causes Fusarium crown rot and Fusarium head blight in wheat. The basic leucine zipper proteins (bZIPs) are evolutionarily conserved transcription factors that play crucial roles in a range of growth and developmental processes and the responses to biotic and abiotic stresses. However, the roles of bZIP transcription factors remains unknown in . In this study, a bZIP transcription factor Fpkapc was identified to localize to the nucleus in . A mutant strain (Δ) was constructed to determine the role of Fpkapc in growth and pathogenicity of . Transcriptomic analyses revealed that many genes involved in basic metabolism and oxidation-reduction processes were downregulated, whereas many genes involved in metal iron binding were upregulated in the Δ strain, compared with the wild type (WT). Correspondingly, the mutant had severe growth defects and displayed abnormal hyphal tips. Conidiation in the mutant was reduced, with more conidia in smaller size and fewer septa than in the WT. Also, relative to WT, the Δ strain showed greater tolerance to ion stress, but decreased tolerance to HO. The mutant caused smaller disease lesions on wheat and barley plants, but significantly increased gene expression, compared with the WT. In summary, Fpkapc plays multiple roles in governing growth, development, stress responses, and virulence in .
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http://dx.doi.org/10.1094/PHYTO-12-21-0520-RDOI Listing
June 2022

Clinical Characteristics for the Improvement of Cushing's Syndrome Complicated With Cardiomyopathy After Treatment With a Literature Review.

Front Cardiovasc Med 2021 1;8:777964. Epub 2021 Dec 1.

Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.

Endogenous Cushing's syndrome (CS), also called hypercortisolism, leads to a significant increase in mortality due to excessive cortisol production, which is mainly due to cardiovascular disease. CS complicated with cardiomyopathies, which is a rare and severe condition, has rarely been reported in the literature. To investigate the clinical characteristics of CS complicated with cardiomyopathies, we retrospectively reviewed the clinical manifestations, laboratory results, cardiac imaging results and prognosis to further understand the diagnosis, treatment, and management of these cases. The clinical data of patients diagnosed with CS complicated with cardiomyopathies obtained from discharge sheets from Peking Union Medical College Hospital from January 1986 to August 2021 were collected. Case reports of CS complicated with cardiomyopathies were retrieved from PubMed. In addition, Cushing's disease (CD) patients without cardiomyopathies were collected as controls to compare the clinical features. A total of 19 cases of CS complicated with cardiomyopathies and cases of CD without cardiomyopathies ( = 242) were collected. The causes of CS included pituitary adenoma ( = 8, 42.11%), adrenal adenoma ( = 7, 36.84%), ectopic adrenocorticotropic hormone (ACTH) tumor ( = 2, 10.53%) and unclear causes ( = 2, 10.53%) in the CS complicated with cardiomyopathies group. The types of cardiomyopathies were dilated cardiomyopathies ( = 15, 78.94%) and hypertrophic cardiomyopathies ( = 4, 21.05%). The serum sodium concentration was significantly higher [145.50 (140.50-148.00) mmol/L vs. 141.00 (140.00-143.00) mmol/L], while the serum potassium concentration was significantly lower [2.70 (2.40-3.60) mmol/L] vs. 3.90 (3.50-4.20 mmol/L)] in the CS complicated with cardiomyopathies group compared to the CD patients without cardiomyopathies. There were no significant differences between the CS complicated with cardiomyopathies group and the CD patients without cardiomyopathies in the serum cortisol concentration and 24-h urine free cortisol, but a significant difference in the adrenocorticotropic hormone level [109.00 (91.78-170.30) pg/ml vs. 68.60 (47.85-110.00) pg/ml]. Twelve/16 (75.0%) patients showed significant improvement or even a complete healing of the heart structure and function after remission of hypercortisolemia after treatment with CS. CS complicated with cardiomyopathies is a very rare clinical entity, in which cortisol plays an important role and it can be greatly improved after remission of hypercortisolemia.
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http://dx.doi.org/10.3389/fcvm.2021.777964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8671741PMC
December 2021

Serum Metabolomics Reveals Dysregulation and Diagnostic Potential of Oxylipins in Tumor-induced Osteomalacia.

J Clin Endocrinol Metab 2022 04;107(5):1383-1391

Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.

Context: Excessive production of fibroblast growth factor 23 (FGF23) by a tumor is considered the main pathogenesis in tumor-induced osteomalacia (TIO). Despite its importance to comprehensive understanding of pathogenesis and diagnosis, the regulation of systemic metabolism in TIO remains unclear.

Objective: We aimed to systematically characterize the metabolome alteration associated with TIO.

Methods: By means of liquid chromatography-tandem mass spectrometry-based metabolomics, we analyzed the metabolic profile from 96 serum samples (32 from TIO patients at initial diagnosis, pairwise samples after tumor resection, and 32 matched healthy control (HC) subjects). In order to screen and evaluate potential biomarkers, statistical analyses, pathway enrichment and receiver operating characteristic (ROC) were performed.

Results: Metabolomic profiling revealed distinct alterations between TIO and HC cohorts. Differential metabolites were screened and conducted to functional clustering and annotation. A significantly enriched pathway was found involving arachidonic acid metabolism. A combination of 5 oxylipins, 4-HDoHE, leukotriene B4, 5-HETE, 17-HETE, and 9,10,13-TriHOME, demonstrated a high sensitivity and specificity panel for TIO prediction screened by random forest algorithm (AUC = 0.951; 95% CI, 0.827-1). Supported vector machine modeling and partial least squares modeling were conducted to validate the predictive capabilities of the diagnostic panel.

Conclusion: Metabolite profiling of TIO showed significant alterations compared with HC. A high-sensitivity and high-specificity panel with 5 oxylipins was tested as diagnostic predictor. For the first time, we provide the global profile of metabolomes and identify potential diagnostic biomarkers of TIO. The present work may offer novel insights into the pathogenesis of TIO.
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http://dx.doi.org/10.1210/clinem/dgab885DOI Listing
April 2022

Bone Geometry, Density, Microstructure, and Biomechanical Properties in the Distal Tibia in Patients With Primary Hypertrophic Osteoarthropathy Assessed by Second-Generation High-Resolution Peripheral Quantitative Computed Tomography.

J Bone Miner Res 2022 03 3;37(3):484-493. Epub 2022 Jan 3.

Department of Endocrinology, Key Laboratory of Endocrinology, NHC, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.

Periosteosis refers to pathological woven bone formation beneath the cortical bone of the long bones. It is an imaging hallmark of primary hypertrophic osteoarthropathy (PHO) and also considered as one of the major diagnostic criteria of PHO patients. Up to date, detailed information on bone quality changes in long bones of PHO patients is still missing. This study aimed to evaluate bone microarchitecture and bone strength in PHO patients by using high-resolution peripheral quantitative computed tomography (HR-pQCT). The study comprised 20 male PHO patients with the average age of 27.0 years and 20 age- and sex-matched healthy controls. The areal bone mineral density (aBMD) was assessed at the lumbar spine (L -L ) and hip (total hip and femoral neck) by dual-energy X-ray absorptiometry (DXA). Bone geometry, volumetric bone mineral density (vBMD), and microstructure parameters at the distal tibia were evaluated by using HR-pQCT. Bone strength was evaluated by finite element analysis (FEA) based on HR-pQCT screening at distal tibia. Urinary prostaglandin E (PGE ), serum phosphatase (ALP), beta-C-telopeptides of type I collagen (β-CTX), soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteoprotegerin (OPG), and neuronal calcitonin gene-related peptide (CGRP) were investigated. As compared with healthy controls, PHO patients had larger bone cross-sectional areas; lower total, trabecular, and cortical vBMD; compromised bone microstructures with more porous cortices, thinned trabeculae, reduced trabecular connectivity, and relatively more significant resorption of rod-like trabeculae at distal tibia. The apparent Young's modulus was significantly lower in PHO patients. The concentration of PGE , biomarkers of bone resorption (β-CTX and sRANKL/OPG ratio), and the neuropeptide CGRP were higher in PHO patients versus healthy controls. PGE level correlated negatively with vBMD and estimated bone strength and positively with bone geometry at distal tibia. The present HR-pQCT study is the first one illustrating the microarchitecture and bone strength features in long bones. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4488DOI Listing
March 2022

Clinical, Biochemical, Radiological, and Genetic Analyses of a Patient with VCP Gene Variant-Induced Paget's Disease of Bone.

Calcif Tissue Int 2022 04 20;110(4):518-528. Epub 2021 Nov 20.

Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Shuaifuyuan No.1, Dongcheng District, Beijing, 100730, China.

Paget's disease of bone (PDB) is a rare metabolic bone disorder, which is extremely rare in Asian population. This study aimed to investigate the phenotypes and the pathogenic mutations of woman with early-onset PDB. The clinical features, bone mineral density, x-ray, radionuclide bone scan, and serum levels of alkaline phosphatase (ALP), procollagen type 1 N-terminal propeptide (P1NP), and β-carboxy-terminal cross-linked telopeptide of type 1 collagen (β-CTX) were measured in detail. The pathogenic mutations were identified by whole-exon sequencing and confirmed by Sanger sequencing. We also evaluated the effects of intravenous infusion of zoledronic acid on the bones of the patient and summarized the phenotypic characteristics of reported patients with mutation at position 155 of the valosin-containing protein (VCP). The patient only exhibited bone pain as the initial manifestation with vertebral compression fracture and extremely elevated ALP, P1NP, and β-CTX levels; she had no inclusion body myopathy and frontotemporal dementia. The missense mutation in exon 5 of the VCP gene (p.Arg155His) was identified by whole-exome sequencing and further confirmed by Sanger sequencing. No mutation in candidate genes of PDB, such as SQSTM1, CSF1, TM7SF4, OPTN, PFN1, and TNFRSF11A, were identified in the patient by Sanger sequencing. Rapid relief of bone pain and a marked decline in ALP, P1NP, and β-CTX levels were observed after zoledronic acid treatment. Previously reported patients with VCP missense mutation at position 155 (R155H) always had myopathy, frontotemporal dementia, and PDB, but the patient in this study exhibited only PDB. This was the first report of R155H mutation-induced early-onset in the VCP gene in Asian population. PDB was the only manifestation having a favorable response to zoledronic acid treatment. We broadened the genetic and clinical phenotype spectra of the VCP mutation.
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http://dx.doi.org/10.1007/s00223-021-00929-xDOI Listing
April 2022

Bone Impairment in a Large Cohort of Chinese Patients With Tumor-Induced Osteomalacia Assessed by HR-pQCT and TBS.

J Bone Miner Res 2022 03 3;37(3):454-464. Epub 2022 Jan 3.

Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by excessive production of fibroblast growth factor 23 (FGF23) by a tumor. Previous studies have revealed generalized mineralization defects and low areal bone mineral density (aBMD) in TIO. However, data on the bone microarchitecture in TIO are limited. In this study, we evaluated the microarchitecture in the peripheral (distal radius and tibia) and axial (lumbar spine) skeleton using high-resolution peripheral quantitative computed tomography (HR-pQCT) and trabecular bone score (TBS) and investigated related factors in a large cohort of Chinese patients with TIO. A total of 186 patients with TIO who had undergone dual-energy X-ray absorptiometry (DXA) or HR-pQCT scans were enrolled. Compared with age-, sex-, and body mass index (BMI)-matched healthy controls, TIO patients (n = 113) had lower volumetric BMD, damaged microstructure, and reduced bone strength in the peripheral skeleton, especially at the tibia. The average TBS obtained from 173 patients was 1.15 ± 0.16. The proportion of patients with abnormal TBS (<1.35) was higher than that with low L to L aBMD Z-score (Z ≤ -2) (43.9% versus 89.6%, p < 0.001). Higher intact fibroblast growth factor 23 (iFGF23), intact parathyroid hormone (iPTH), alkaline phosphatase, and β-isomerized C-terminal telopeptide of type I collagen (β-CTx) levels, more severe mobility impairment, and a history of fracture were associated with poorer HR-pQCT parameters but not with lower TBS. However, greater height loss and longer disease duration were correlated with worse HR-pQCT parameters and TBS. Moreover, TBS was correlated with both trabecular and cortical HR-pQCT parameters in TIO. In conclusion, we revealed impaired bone microarchitecture in the axial and peripheral skeleton in a large cohort of Chinese TIO patients. HR-pQCT parameters and TBS showed promising advantages over aBMD for assessing bone impairment in patients with TIO. A longer follow-up period is needed to observe changes in bone microarchitecture after tumor resection. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4476DOI Listing
March 2022

A novel long-range deletion spanning CDC73 and upper-stream genes discovered in a kindred of familial primary hyperparathyroidism.

Endocrine 2022 Mar 2;75(3):907-915. Epub 2021 Nov 2.

Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100032, China.

Purpose: To confirm the exact break-point of a novel long-range deletion discovered in one female parathyroid carcinoma (PC) patient who has a strong family history suggesting familial hyperparathyroidism, and to investigate the expression of parafibromin in the patient's affected lesion.

Methods: Clinical information of one female patient as well as five of her relatives was collected. Their genomic DNA extracted from peripheral blood went through Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). After completing whole genome sequencing (WGS), clone sequencing was also performed, whose result was aligned with standard human genome database after Sanger sequencing.

Results: The medical history of recurrent hypercalcemia after parathyroidectomy and histopathological investigation confirmed that the female patient was diagnosed with PC. WGS displayed a novel 130 kb long-range deletion spanning UCHL5 to CDC73 that was later confirmed by clone sequencing. MLPA showed similar results in four of her five relatives, suggesting these people to be carriers of the same long-range deletion, and three among them had a history of primary hyperparathyroidism (PHPT) ahead of the proband's first visit.

Conclusions: We discovered a novel 130 kb long-range deletion spanning CDC73 in a family of 5 persons, and the existence of the deletion was related to PHPT and PC. Our discovery validated the role of CDC73 mutation in the occurrence of PHPT and PC, which provided new information to the genetic studies of PC.
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http://dx.doi.org/10.1007/s12020-021-02917-5DOI Listing
March 2022

Clinical, Biochemical, Radiological, Genetic and Therapeutic Analysis of Patients with COMP Gene Variants.

Calcif Tissue Int 2022 03 28;110(3):313-323. Epub 2021 Oct 28.

Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia type 1 (MED1) are two rare skeletal disorders caused by cartilage oligomeric matrix protein (COMP) variants. This study aims to analyze the genotype and phenotype of patients with COMP variants. Clinical information for 14 probands was collected; DNA was extracted from blood for COMP variant detection. Clinical manifestations and radiology scoring systems were established to evaluate the severity of each patient's condition. Serum COMP levels in PSACH patients and healthy subjects were measured. Thirty-nine patients were included, along with 12 PSACH probands and two MED1 probands. Disproportionate short stature, waddling gait, early-onset osteoarthritis and skeletal deformities were the most common features. The height Z-score of PSACH patients correlated negatively with age at evaluation (r =  - 0.603, p = 0.01) and the clinical manifestation score (r =  - 0.556, p = 0.039). Over 50% of the PSACH patients were overweight/obese. The median serum COMP level in PSACH patients was 16.75 ng/ml, which was significantly lower than that in healthy controls (98.53 ng/ml; p < 0.001). The condition of MED1 patients was better than that of PSACH patients. Four novel variants of COMP were detected: c.874T>C, c.1123_1134del, c.1531G>A, and c.1576G>T. Height Z-scores and serum COMP levels were significantly lower in patients carrying mutations located in calmodulin-like domains 6, 7, and 8. As the two phenotypes overlap to different degrees, PSACH and MED1 are suggested to combine to produce "spondyloepiphyseal dysplasia, COMP type". Clinical manifestations and radiology scoring systems, serum COMP levels and genotype are important for evaluating patient condition severity.
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http://dx.doi.org/10.1007/s00223-021-00920-6DOI Listing
March 2022

Alteration of Bone Density, Microarchitecture, and Strength in Patients with Camurati-Engelmann Disease: Assessed by HR-pQCT.

J Bone Miner Res 2022 01 28;37(1):78-86. Epub 2021 Sep 28.

Department of Endocrinology, Key Laboratory of Endocrinology, NHC, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.

Camurati-Engelmann disease (CED) is a rare autosomal-dominant skeletal dysplasia caused by mutations in the transforming growth factor-β1 (TGFB1) gene. In this study, a retrospective review of patients with CED evaluated at Peking Union Medical College Hospital in Beijing, China, between November 30, 2000 and November 30, 2020 was conducted. Data including demographic data, manifestations, and examination results were characterized. Furthermore, bone geometry, density, and microarchitecture were assessed and bone strength was estimated by HR-pQCT. Results showed the median age at onset was 2.5 years. Common manifestations included pain in the lower limbs (94%, 17/18), abnormal gait (89%, 16/18), genu valgum (89%, 16/18), reduced subcutaneous fat (78%, 14/18), delayed puberty (73%, 8/11), muscle weakness (67%, 12/18), hearing loss (39%, 7/18), hepatosplenomegaly (39%, 7/18), exophthalmos or impaired vision or visual field defect (33%, 6/18), and anemia (33%, 7/18). Twenty-five percent (4/16) of patients had short stature. Serum level of alkaline phosphatase was elevated in 41% (7/17) of patients whereas beta-C-terminal telopeptide was elevated in 91% of patients (10/11). Among 12 patients, the Z-scores of two patients were greater than 2.5 at the femur neck and the Z-scores of five patients were lower than -2.5 at the femur neck and/or lumbar spine. HR-pQCT results showed lower volumetric BMD (vBMD), altered bone microstructure and lower estimated bone strength at the distal radius and tibia in patients with CED compared with controls. In addition, total volume bone mineral density and cortical volumetric bone mineral density at the radius were negatively correlated with age in patients with CED, but positively correlated with age in controls. In conclusion, the largest case series of CED with characterized clinical features in a Chinese population was reported here. In addition, HR-pQCT was used to investigate bone microstructure at the distal radius and tibia in nine patients with CED, and the alteration of bone density, microstructure, and strength was shown for the first time. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4436DOI Listing
January 2022

Low Levels of Serum Sclerostin in Adult Patients With Tumor-Induced Osteomalacia Compared With X-linked Hypophosphatemia.

J Clin Endocrinol Metab 2022 01;107(1):e361-e371

Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.

Context: Sclerostin inhibits Wnt-β-catenin signaling, regulating bone formation. Circulating sclerostin was reported to be elevated in X-linked hypophosphatemia (XLH) patients, and sclerostin antibody (Scl-Ab) increased bone mass and normalized circulating phosphate in Hyp mice. However, circulating sclerostin levels in patients with acquired hypophosphatemia due to tumor-induced osteomalacia (TIO) are rarely reported.

Objective: This study was designed to evaluate serum sclerostin levels in TIO patients compared with age- and sex-matched healthy controls and XLH patients to analyze correlations with bone mineral density (BMD) and laboratory parameters.

Methods: This cross-sectional study determined serum sclerostin levels in 190 individuals, comprising 83 adult TIO patients, 83 adult healthy controls and 24 adult XLH patients.

Results: TIO patients (43 male, 40 female) aged 44.3 ± 8.7 (mean ± SD) years had lower levels of circulating sclerostin than controls (94.2 ± 45.8 vs 108.4 ± 42.3 pg/mL, P = 0.01), adjusted for age, gender, BMI, and diabetes rate. Sclerostin levels were positively associated with age (r = 0.238, P = 0.030). Male patients had higher sclerostin than female patients (104.7 ± 47.3 vs 83.0 ± 41.8 pg/mL, P = 0.014). Sclerostin levels were positively associated with L1-4 BMD (r = 0.255, P = 0.028), femoral neck BMD (r = 0.242, P = 0.039), and serum calcium (r = 0.231, P = 0.043). Comparison of sclerostin levels in TIO patients (n = 24, age 35.9 ± 7.3 years) vs XLH patients vs healthy controls revealed significant differences (respectively, 68.4 ± 31.3, 132.0 ± 68.8, and 98.6 ± 41.1 pg/mL, P < 0.001).

Conclusion: Circulating sclerostin was decreased in TIO patients but increased in XLH patients, possibly due to histological abnormality and bone mass.
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http://dx.doi.org/10.1210/clinem/dgab579DOI Listing
January 2022

Spectrum of mitochondrial genomic variation in parathyroid neoplasms.

Endocrine 2021 12 22;74(3):690-697. Epub 2021 Jul 22.

Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Purpose: Mitochondrial DNA (mtDNA) variations have been implicated in various cancer types. Several attempts have been made in benign parathyroid adenoma (PA); however, mtDNA variants and copy number alterations have not been investigated in parathyroid carcinoma (PC). The present study aimed to explore the variations in the mitochondrial genome in parathyroid neoplasms.

Methods: In this study, ultradeep targeted sequencing of mtDNA was performed in 12 cases with PC and 25 cases with PA. Germline and somatic variants in the mitochondrial genome were analysed according to clinical features. The mtDNA copy number relative to nuclear DNA was measured.

Results: A total of 821 germline variants and 23 somatic mutations were identified. All 160 germline nonsynonymous variants in the coding sequence (CDS) were predicted to be likely benign, and germline variants frequently occurred (26.3%) in the displacement loop region. Tumour somatic mutation in a CDS with heteroplasmic factor (HF) >0.8 showed a higher mtDNA copy number (p = 0.039). Using Spearman's rank test, tumour mtDNA copy number revealed a positive correlation with serum levels of intact parathyroid hormone and calcium.

Conclusion: Our results demonstrate that null recurrent mtDNA mutational hotspots were PC specific. An increased mtDNA copy number in parathyroid neoplasms was associated with somatic CDS mutations with a high HF and major clinical features. Larger cohort investigations should be performed in future analyses.
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http://dx.doi.org/10.1007/s12020-021-02825-8DOI Listing
December 2021

Comparative effect of eldecalcitol and alfacalcidol on bone microstructure: A preliminary report of secondary analysis of a prospective trial.

Osteoporos Sarcopenia 2021 Jun 3;7(2):47-53. Epub 2021 Jun 3.

Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.

Objectives: To compare the effect of eldecalcitol and alfacalcidol on skeletal microstructure by high-resolution peripheral QCT (HR-pQCT).

Methods: This was a substudy of a randomized, double-blind, active comparator trial. Five female osteoporotic patients with 1-year 0.75 μg/day eldecalcitol and 5 with 1-year 1.0 μg/day alfacalcidol completed HR-pQCT scans before and after treatment were enrolled.

Results: Total vBMD [1.67 ± 1.06% (mean ± SD), P = 0.043 versus baseline] and trabecular vBMD (2.91 ± 1.72%, P = 0.043) at the radius increased in eldecalcitol group, while total, trabecular, and cortical vBMD tended to decrease in alfacalcidol group, with a significant reduction in cortical vBMD at the tibia (0.88 ± 0.62%, P = 0.043). Cortical area (1.82 ± 1.92%, P = 0.043) at the radius and thickness (0.87 ± 1.12%, P = 0.043) at the tibia increased in eldecalcitol group, while these parameters decreased with alfacalcidol at the tibia (1.77 ± 1.72%, P = 0.043 for cortical area; 1.40 ± 2.14%, P = 0.042 for cortical thickness). Trabecular thickness at the radius (1.97 ± 1.93%, P = 0.042) and number at the tibia (3.09 ± 3.04%, P = 0.043) increased by eldecalcitol but did not increase by alfacalcidol. Trabecular separation decreased by eldecalcitol (2.22 ± 2.43%, P = 0.043) but tended to increase by alfacalcidol at the tibia.

Conclusions: Eldecalcitol has the greater potential to improve cortical and trabecular microstructure at the peripheral bone than alfacalcidol which needs further more studies.
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http://dx.doi.org/10.1016/j.afos.2021.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261726PMC
June 2021

Health-related quality of life in men with osteoporosis: a systematic review and meta-analysis.

Endocrine 2021 11 24;74(2):270-280. Epub 2021 Jun 24.

Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shuaifuyuan No. 1, Dongcheng District, Beijing, China.

Purpose: The increased social and economic burdens make osteoporosis in men an emerging public health issue. However, the quality of life among men with osteoporosis is still unclear. This systematic review and meta-analysis aimed to evaluate the health-related quality of life (HRQoL) among men with osteoporosis or osteoporotic fracture.

Methods: PubMed, EMBASE, and the Cochrane Library database were systematically searched from inception to May 2021. Studies were included if they used validated questionnaires to measure HRQoL among osteoporotic men. A meta-analysis was performed using a random-effects model or fixed-effects model to calculate the standard mean difference (SMD) or mean difference (MD) with 95% confidential interval (95% CI).

Results: 14 studies involving 6338 male participants were chosen for systematic review, of which 10 were included in the meta-analysis. Men with osteoporosis had poorer global HRQoL and multiple dimensions of HRQoL than men without osteoporosis. Hip fracture, vertebral fractures, or wrist fractures dramatically impaired HRQoL of men, and physical function was declined even before hip fracture (SMD = -0.60, 95% CI, -0.82 to -0.39). Femoral and lumbar BMD was positively correlated with HRQoL, and a number of fragility fractures and time since fracture had negative effects on HRQoL. Effective anti-osteoporotic drugs could improve HRQoL of men.

Conclusion: The health-related life quality of men was significantly impaired by osteoporosis and fracture of the hip, vertebral, or wrist. We should pay more attention to the diagnosis and treatment of male osteoporosis to improve the life quality of men.
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http://dx.doi.org/10.1007/s12020-021-02792-0DOI Listing
November 2021

Early Discrimination Between Tumor-Induced Rickets/Osteomalacia and X-Linked Hypophosphatemia in Chinese Children and Adolescents: A Retrospective Case-Control Study.

J Bone Miner Res 2021 09 19;36(9):1739-1748. Epub 2021 May 19.

Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China.

In children and adolescents, distinguishing tumor-induced rickets/osteomalacia (TIR/O) from hereditary hypophosphatemic rickets/osteomalacia (HR/O) is a medical challenge. We retrospectively studied 10 Chinese children and adolescents with TIR/O who underwent surgery at a mean age of 17.4 ± 2.1 years and compared their characteristics to 24 age- and sex-matched patients with X-linked hypophosphatemia (XLH). Positive family history of HR/O and dental problems, such as enamel hypoplasia and dental abscess, were reported in 8 (33.3%) and 5 (20.8%) patients with XLX, respectively, but not in patients with TIR/O. In addition, in comparison with XLH patients, TIR/O patients had an older disease onset age (150 versus 24 months, p < 0.001), a higher height standard deviation score (SDS; -1.2 ± 1.8 versus -4.0 ± 1.4, p < 0.001), a lower Z-score of bone mineral density (BMD) at lumbar spine (LS) (-3.9 [6.0] versus +1.8 [7.0], p < 0.001), and a higher serum intact fibroblast growth factor 23 (FGF23) level (500.27 ± 87.20 versus 121.71 ± 70.94 pg/mL, p < 0.001), corresponding to a lower serum phosphate level (0.52 ± 0.07 versus 0.64 ± 0.11 mmol/L, p = 0.005) and a higher serum alkaline phosphatase (ALP) level (557 [631] versus 305 [249] U/L, p = 0.005). We generated receiver operating characteristic (ROC) curves and calculated the area under the ROC curve (AUC). The AUCs of onset age, FGF23, and LS Z-score were equal to 1, suggesting that these are excellent indices for the differential diagnosis between TIR/O and XLH. In summary, our study furthers our understanding of the spectrum of clinical, biochemical, and pathologic findings associated with TIR/O. For children and adolescent patients with HR/O, a comprehensive and careful clinical and laboratory evaluation is of great importance, and we recommend enquiry of the family history, onset age, and dental problems, as well as measurement of serum FGF23 and BMD. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4331DOI Listing
September 2021

Bone turnover markers are associated with the PTH levels in different subtypes of pseudohypoparathyroidism type 1 patients.

Clin Endocrinol (Oxf) 2021 08 19;95(2):277-285. Epub 2021 May 19.

Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences (CAMS), Beijing, China.

Objective: Bone responsiveness to parathyroid hormone (PTH) in different subtypes of pseudohypoparathyroidism type 1 (PHP1) remains controversial. We aimed to investigate this phenomenon using bone turnover markers (BTMs) in a large cohort of PHP1 patients.

Design: Retrospective study.

Patients: Sixty-three PHP1 patients diagnosed by molecular analysis were used as subjects, and 48 sex- and age-matched patients with nonsurgical hypoparathyroidism (NS-HP) were used for comparison.

Measurements: Bone turnover markers, alkaline phosphatase (ALP), C-terminal telopeptide of type I collagen (β-CTX) and related parameters in PHP1 were compared among different subtypes and with NS-HP.

Results: Among all the PHP1 patients (15 PHP1A, 14 familial 1B and 34 sporadic 1B), 23.8% had elevated baseline BTM levels. No significant difference was found in the β-CTX levels among different subtypes. The β-CTX level was positively correlated with the PTH level for all PHP1, PHP1B and PHP1A patients (B = 0.001, 0.001 and 0.004, respectively; all p < .05). The BTM levels of PHP1 patients were significantly higher than those of NS-HP patients (β-CTX: 0.56 ng/ml vs. 0.20 ng/ml, p = .001; ALP: 105 U/L vs. 72 U/L, p = .001). The serum β-CTX levels in different PHP1 subtypes were all significantly higher than those in NS-HP patients in adults. Among the 22 followed up patients, changes in BTMs were associated with changes in PTH (β-CTX: r = .507, p = .023; ALP: r = .475, p = .034).

Conclusions: Bone tissues respond to PTH in different PHP1 subtypes, and it is reasonable to monitor and normalize PTH and BTMs in addition to the serum and urinary calcium levels in the follow-up of PHP1 patients.
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http://dx.doi.org/10.1111/cen.14496DOI Listing
August 2021

Cushing's Syndrome With Nocardiosis: A Case Report and a Systematic Review of the Literature.

Front Endocrinol (Lausanne) 2021 29;12:640998. Epub 2021 Mar 29.

Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China.

Objective: To analyze and summarize the clinical characteristics, treatments, and prognosis of Cushing's syndrome (CS) with nocardiosis.

Methods: A patient in our hospital and additional 17 patients of CS with nocardiosis in the English literature were included in this study. Clinical characteristics, laboratory data, imaging studies, treatments, and prognosis were evaluated.

Results: A 41-year-old man with CS was diagnosed and treated in our hospital. He had co-infections of nocardiosis and aspergillosis. Together with 17 patients of CS with nocardiosis in the English literature, 2 patients (11.1%) were diagnosed as Cushing's disease (CD) while 16 (88.9%) were diagnosed or suspected as ectopic ACTH syndrome (EAS). The average 24hrUFC was 7,587.1 ± 2,772.0 μg/d. The average serum total cortisol and ACTH (8 AM) was 80.2 ± 18.7 μg/dl and 441.8 ± 131.8 pg/ml, respectively. The most common pulmonary radiologic findings in CT scan were cavitary lesions (10/18) and nodules (8/18). Co-infections were found in 33.3% (6/18) patients. The CS patients with co-infections had higher levels of ACTH (671.5 ± 398.2 245.5 ± 217.1 pg/ml, = 0.047), and 38.9% (7/18) patients survived through the antibiotic therapy and the treatment of CS. Patients with lower level of ACTH (survival mortality: 213.1 ± 159.0 554.7 ± 401.0 pg/ml, P = 0.04), no co-infection, underwent CS surgery, and received antibiotic therapy for more than 6 months, had more possibilities to survive.

Conclusions: Nocardia infection should be cautioned when a patient of CS presented with abnormal chest radiographs. The mortality risk factors for CS with nocardiosis are high level of ACTH and co-infections. We should endeavor to make early etiological diagnosis, apply long-term sensitive antibiotics and aggressive treatments of CS.
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http://dx.doi.org/10.3389/fendo.2021.640998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040973PMC
January 2022

Associations between Osteocalcin, Calciotropic Hormones, and Energy Metabolism in a Cohort of Chinese Postmenopausal Women: Peking Vertebral Fracture Study.

Int J Endocrinol 2021 24;2021:5585018. Epub 2021 Mar 24.

Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, No. 1 Shuaifuyuan, Wangfujing Street, Dongcheng District, Beijing 100730, China.

Objective: The endocrine function of bone in energy metabolism may be mediated by the osteocalcin (OC). We examined the association between OC and energy metabolism among Chinese postmenopausal women. . A cross-sectional cohort study enrolling 1635 participants was conducted using data from the Peking Vertebral Fracture study. Partial correlation analysis was performed to explore the correlation of OC, parathyroid hormone (PTH), or 25-hydroxyvitamin (25(OH)D) with glycemic and lipid metabolic parameters. A logistic regression model was used to investigate the association of OC, PTH, or 25(OH)D with the prevalence of diabetes and dyslipidemia.

Results: Serum levels of OC, PTH, and 25(OH)D were all positively correlated with serum cholesterol levels, whereas only OC was negatively associated with serum glucose level. In the logistic regression model, both OC and PTH were negatively associated with the prevalence of diabetes (odds ratio [OR], 95% confidence interval [95% CI]: 0.967, 0.948-0.986 for OC and 0.986, 0.978-0.994 for PTH). No significant association was found between 25(OH)D and diabetes. Both OC and 25(OH)D, rather than PTH, were associated with abnormalities of high cholesterol levels, such as hypercholesterolemia and high LDL-C levels. Further classifying the population based on the median value of OC and PTH, low OC and low PTH subgroup had the highest OR, 95% CI for diabetes (1.873, 1.287-2.737) and the lowest OR, 95% CI for hypercholesterolemia (0.472, 0.324-0.688) and for high LDL-C (0.538, 0.376-0.771).

Conclusion: Among Chinese postmenopausal women, a lower serum level of OC was associated with a higher prevalence of diabetes and lower serum cholesterol levels, and a low PTH concentration could magnify these associations.
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http://dx.doi.org/10.1155/2021/5585018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016567PMC
March 2021

Experience of Ectopic Adrenocorticotropin Syndrome: 88 Cases With Identified Causes.

Endocr Pract 2021 Sep 9;27(9):866-873. Epub 2021 Mar 9.

Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.

Objective: Ectopic adrenocorticotropic hormone syndrome (EAS) is a rare cause of Cushing's syndrome and diagnosis and management remain challenging. The aim of this study was to present the clinical spectrum of a group of EAS cases in a single center to explore better management strategies.

Methods: A retrospective study was conducted to identify 88 confirmed EAS cases at our hospital from 1984 to 2019. The clinical, biochemical, imaging, and pathological features were analyzed.

Results: Of the 88 eligible patients with EAS, 38 (43.2%) cases of pulmonary neuroendocrine tumors (NETs) and a larger number of thymic/mediastinal NETs (29 cases, 33%) were identified. The clinical and biological features of EAS and Cushing's disease overlapped but were more severe in EAS. Inferior petrosal sinus sampling (97.4%) and computed tomography (85.4%) provided the highest positive diagnostic accuracy. Computed tomography is also a useful tool to identify tumors in chest cavity compared with nonchest lesions (91.2% vs 57.1%). Although a greater tumor size (4.54 cm vs 1.44 cm) and higher rate of insuppressible high-dose dexamethasone suppression test (83.3% vs 51.5%) were found in thymic/mediastinum NETs than in pulmonary NETs, the level of hormone production had no difference.

Conclusion: EAS had more common and severe clinical presentations than Cushing's disease, and multiple imaging approaches are required for reliable diagnosis. A higher proportion of thymic/mediastinal NETs was found in our study. For patients without a certain tumor source, long-term follow-up and further evaluations are needed.
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http://dx.doi.org/10.1016/j.eprac.2021.02.015DOI Listing
September 2021

Germline GCM2 Mutation Screening in Chinese Primary Hyperparathyroidism Patients.

Endocr Pract 2020 Oct;26(10):1093-1104

From the Key laboratory of Endocrinology, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. Electronic address:

Objective: Glial cell missing 2 (GCM2), the critical regulator in the development of parathyroid glands, has been associated with the pathogenesis of primary hyperparathyroidism (PHPT). Relevant data in Chinese and other Asian populations are still lacking. This study aimed to screen the germline mutations of GCM2 in Chinese PHPT patients.

Methods: A total of 232 patients diagnosed with PHPT at the Peking Union Medical College Hospital from July, 2016, to February, 2019, were screened using targeted next-generation sequencing to identify rare variants of 8 candidate genes associated with PHPT, including GCM2. Luciferase assays were performed to determine the functional impact of the GCM2 variants.

Results: Four male patients were found to carry 3 rare missense variants of the GCM2 gene, including c.1162A>G (p.K388E), c.1144G>A (p.V382M), and c.1247A>G (p.Y416C). Two variants (p.K388E and p.V382M) located within a highly conserved region were associated with GCM2 transactivation function. The 2 cases carrying the p.K388E mutation had a pathology of carcinoma, and the case with the p.V382M mutation had atypical adenoma.

Conclusion: This study determined an overall GCM2 gain-of-function mutation frequency of 1.3% in a relatively large-sample-sized Chinese PHPT cohort and supported a higher malignant tendency in cases carrying activating GCM2 mutations. Hence, preoperative screening for these GCM2 mutations might be beneficial to treatment decisions, and longer follow-up for such patients is recommended.
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http://dx.doi.org/10.4158/EP-2020-0132DOI Listing
October 2020
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