Search

We developed a new tool to assess the severity of osteoporotic vertebral fracture using radiographs of the spine. Our technique can be used in patient care by helping to stratify patients with osteoporotic vertebral fractures into appropriate treatment pathways. It can also be used for research purposes., Purpose: The aim of our study was to propose a semi-quantitative (SQ) grading scheme for osteoporotic vertebral fracture (OVF) on anteroposterior (AP) radiographs., Methods: On AP radiographs, the vertebrae are divided into right and left halves, which are graded (A) vertical rectangle, (B) square, (C) traverse rectangle, and (D) trapezoid; whole vertebrae are graded (E) transverse band or (F) bow-tie. Type A and B were compared with normal and Genant SQ grade 1 OVF, Type C and D with grade 2 OVF, and Type E and F with grade 3 OVF. Spine AP radiographs and lateral radiographs of 50 females were assessed by AP radiographs SQ grading. After training, an experienced board-certified radiologist and a radiology trainee assessed the 50 AP radiographs., Results: The height-to-width ratio of the half vertebrae varied 1.32-1.48. On lateral radiographs, 84 vertebrae of the 50 patients had OVFs (38 grade 1, 24 grade 2, and 22 grade 3). On AP radiographs, the radiologist correctly assigned 84.2%, 91.7%, and 77.2% and the trainee correctly assigned 68.4%, 79.2%, and 81.8% of grade 1, 2, and 3 OVFs, respectively. Compared with lateral radiographs, the radiologist had a weighted Kappa of 0.944 including normal vertebrae and 0.883 not including normal vertebrae, while the corresponding Kappa values for the trainee were 0.891 and 0.830, respectively., Conclusion: We propose a new semi-quantitative grading system for vertebral fracture severity assessment on AP spine radiographs., (© 2024. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

The organic anion-transporting polypeptide 1B3 and P-glycoprotein (P-gp) provide efficient directional transport (OATP1B3-P-gp) from the blood to the bile that serves as a key determinant of hepatic disposition of the drug. Unfortunately, there is still a lack of effective means to evaluate the disposal ability mediated by transporters. The present study was designed to identify a suitable endogenous biomarker for the assessment of OATP1B3-P-gp function in the liver. We established stably transfected HEK293T-OATP1B3 and HEK293T-P-gp cell lines. Results showed that azelaic acid (AzA) was an endogenous substrate for OATP1B3 and P-gp using serum pharmacology combined with metabolomics. There is a good correlation between the serum concentration of AzA and probe drugs of rOATP1B3 and rP-gp when rats were treated with their inhibitors. Importantly, after 5-fluorouracil-induced rat liver injury, the relative mRNA level and expression of rOATP1B3 and rP-gp were markedly down-regulated in the liver, and the serum concentration of AzA was significantly increased. These observations suggest that AzA is an endogenous substrate of both OATP1B3 and P-gp, and may serve as a potential endogenous biomarker for the assessment of the function of OATP1B3-P-gp for the prediction of changes in the pharmacokinetics of drugs transported by OATP1B3-P-gp in liver disease states., (© 2024. The Author(s).)

Purpose: Lipocalin 2 (LCN2) is a newly recognized bone-derived factor that is important in regulation of energy metabolism. We investigated the correlation of serum LCN2 levels and glycolipid metabolism, and body composition in a large cohort of patients with osteogenesis imperfecta (OI)., Methods: A total of 204 children with OI and 66 age- and gender-matched healthy children were included. Circulating levels of LCN2 and osteocalcin were measured by enzyme-linked immunosorbent assay. Serum levels of fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), and low- and high-density lipoprotein cholesterol (LDL-C, HDL-C) were measured by automated chemical analyzers. The body composition was measured by dual-energy X-ray absorptiometry. Grip strength and timed-up-and-go (TUG) were tested to evaluate the muscle function., Results: Serum LCN2 levels were 37.65 ± 23.48 ng/ml in OI children, which was significantly lower than those in healthy control (69.18 ± 35.43 ng/ml, P < 0.001). Body mass index (BMI) and serum FBG level were significantly higher and HDL-C levels were lower in OI children than healthy control (all P < 0.01). Grip strength was significantly lower (P < 0.05), and the TUG was significantly longer in OI patients than healthy control (P < 0.05). Serum LCN2 level was negatively correlated to BMI, FBG, HOMA-IR, HOMA-β, total body, and trunk fat mass percentage, and positively correlated to total body and appendicular lean mass percentage (all P < 0.05)., Conclusions: Insulin resistance, hyperglycemia, obesity, and muscle dysfunction are common in OI patients. As a novel osteogenic cytokine, LCN2 deficiency may be relevant to disorders of glucose and lipid metabolism, and dysfunction of muscle in OI patients., (© 2023. The Author(s).)

Background: Osteoporotic vertebral fractures cause pain and disability, which result in a heavy socioeconomic burden. However, the incidence and cost of vertebral fractures in China are unknown. We aimed to assess the incidence and cost of clinically recognized vertebral fractures among people aged 50 years and older in China from 2013 to 2017., Materials and Methods: This population-based cohort study was conducted by using Urban Employee Basic Medical Insurance (UEBMI) and Urban Resident Basic Medical Insurance (URBMI) data in China from 2013 to 2017, which covered more than 95% of the Chinese population in urban areas. Vertebral fractures were identified by the primary diagnosis (i.e. International Classification of Diseases code or text of diagnosis) in UEBMI and URBMI. The incidence and medical cost of these clinically recognized vertebral fractures in urban China were calculated., Results: A total of 271 981 vertebral fractures (186 428, 68.5% females and 85 553, 31.5% males) were identified, with a mean age of 70.26 years. The incidence of vertebral fractures among patients aged 50 years and over in China increased ~1.79-fold during the 5 years, from 85.21 per 100 000 person-years in 2013 to 152.13 per 100 000 person-years in 2017. Medical costs for vertebral fractures increased from US$92.74 million in 2013 to US$505.3 million in 2017. Annual costs per vertebral fracture case increased from US$3.54 thousand in 2013 to US$5.35 thousand in 2017., Conclusion: The dramatic increase in the incidence and cost of clinically recognized vertebral fractures among patients aged 50 and over in urban China implies that more attention should be given to the management of osteoporosis to prevent osteoporotic fractures., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Progressive pseudorheumatoid dysplasia (PPRD) is a rare genetic disease with autosomal recessive inheritance. There was a lack of genotype-phenotype correlation data from the Chinese population. This study aimed to identify the genotype and phenotype characteristics of Chinese PPRD patients and to conduct a genotype-phenotype analysis of Chinese PPRD patients., Methods: Genetic analysis was performed for suspected PPRD patients from Peking Union Medical College Hospital. Medical records were collected from the electronic medical record system and patient-held portable health records. Published Chinese PPRD cases were gathered from both international and Chinese local databases. We collected demographic information, genetic variants, clinical manifestations, and imaging characteristics for further analysis., Results: We included 105 Chinese PPRD patients in the current study. Thirty-three variants, including nine novels and five hotspot variants, were identified, with 26/33 (79%) variants exclusively seen in the Chinese population. Chinese PPRD patients share a phenotype similar to that in international reports. Joint involvement may progress with age (R 2  = 0.2541). Long bone shortening and severe deformities occur in three patients with biallelic null variants, of which at least one variant is located in exon 2. Among hotspot variants, c.624dupA (p.C209Mfs*21) were associated with later onset and more involved joints. Elbow joints were more likely to be affected in patients carrying c.624dupA (p.C209Mfs*21) and c.866dupA (p.S209Efs*13). Shoulder joints are more likely to be involved in patients with biallelic null variants (P = 0.027)., Conclusions: Chinese PPRD patients share a unique mutation spectrum. Among the five hotspot variants, c.624dupA is associated with later onset of disease, more extensive joint involvement, and a tendency to affect elbow joints. Biallelic null variants with at least one variant in exon 2 could be a likely cause of long bone shortening and severe deformities., (© 2023. The Author(s).)

This study takes Cushing's syndrome, a rare disease, as a model, and adopts the path of "Plan, Do, Check, Action" (PDCA) to explore new methods to optimize the clinical path, can improve the quality and efficiency of diagnosis and treatment of rare diseases. After sorting out the problems existing in the previous diagnosis and treatment mode, our team optimizes the path in various ways and establishes a standard operation procedure (SOP) for the new path. In the evaluation of the optimized mode, 55 patients with Cushing's syndrome were admitted to the Department of Endocrinology, Peking Union Medical College Hospital, including 19 males and 36 females, aged (41.8±14.4) years (6-68 years). The pathway group (28 cases) and the control group (27 cases) were divided according to whether they were included in the new path management at the time of admission, and the effect of path optimization was assessed in terms of time, efficacy, safety and cost. The results showed that compared with the control group, the pathway group had a shorter time of hospitalization in the Department of Endocrinology and critical tests, such as blood cortisol rhythm, low-dose dexamethasone inhibition test, and bilateral inferior petrosal sinus sampling (all P <0.05). There was no significant differences in the decrease of total cortisol after operation, the incidence of postoperative complications, and hospitalization expenses (all P >0.05). The optimized path improves the medical efficiency while ensuring medical quality, safety and no increase in cost. This study proposes PDCA path optimization for complex diseases and establishes SOP process, which provides experience in management optimization for the patient-centered and clinical path-oriented diagnosis and treatment mode of rare diseases.

Plastin 3 (PLS3), a protein involved in formation of filamentous actin (F-actin) bundles, is important in human bone health. Recent studies identify PLS3 as a novel bone regulator and PLS3 mutations can lead to a rare monogenic early-onset osteoporosis. However, the mechanism of PLS3 mutation leading to osteoporosis is unknown, and its effective treatment strategies have not been established. Here, we have constructed a novel rat model with clinically relevant hemizygous E10-16del mutation in PLS3 ( PLS3 E10-16del/0 ) that recapitulates the osteoporotic phenotypes with obviously thinner cortical thickness, significant decreases in yield load, maximum load, and breaking load of femora at 3, 6, 9 months old compared to wild-type rats. Histomorphometric analysis indicates a significantly lower mineral apposition rate in PLS3 E10-16del/0 rats. Treatment with alendronate (1.0 µg/kg/day) or teriparatide (40 µg/kg five times weekly) for 8 weeks significantly improves bone mass and bone microarchitecture, and bone strength is significantly increased after teriparatide treatment (p＜0.05). Thus, our results indicate that PLS3 plays an important role in the regulation of bone microstructure and bone strength, and we provide a novel animal model for the study of X-linked early-onset osteoporosis. Alendronate and teriparatide treatment could be a potential treatment for early-onset osteoporosis induced by PLS3 mutation., Competing Interests: JH, BZ, XL, QZ, FG, LS, JL, OW, YJ, WX, XX, ML No competing interests declared, (© 2023, Hu et al.)

Introduction: Osteoporosis leads to more serious consequences in men than in women, but less is known about its impacts on health-related quality of life (HRQoL) of men, and whether the anti-osteoporosis treatment can improve HRQoL of men with osteopenia/osteoprosis., Methods: We enrolled men with primary osteoporosis and age-matched healthy controls. We collected medical history, serum levels of carboxyl-terminal type I collagen telopeptide, procollagen type I propeptides, and bone mineral density of patients. All patients and controls completed the short-form 36 (SF-36) questionnaires. Changes in HRQoL of osteopenia/osteoporosis men were prospectively evaluated after alendronate or zoledronic acid treatment., Results: A total of 100 men with primary osteoporosis or osteopenia and 100 healthy men were included. The patients were divided into three subgroups: osteopenia (n = 35), osteoporosis (n = 39) and severe osteoporosis (n = 26). Men with osteoporosis or severe osteoporosis had impaired HRQoL in domains of physical health compared to healthy controls. HRQoL scores in physical health related domains of patients with severe osteoporosis were significantly lower compared to healthy controls, and were the poorest among the three subgroups of patients. Fragility fracture history was correlated with lower SF-36 scores about physical health. In 34 men with newly diagnosed osteoporosis receiving bisphosphonates treatment, HRQoL scores were significantly improved in domains of physical health after treatments., Conclusions: The HRQoL is significantly impaired in men with osteoporosis, and the more severe the osteoporosis, the poorer the HRQoL. Fragility fracture is an important influencing factor of deteriorated HRQoL. Bisphosphonates treatment is beneficial to improve HRQoL of osteopenia/osteoporosis men., (© 2023. The Author(s).)

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients present with progressive bone pain, muscle weakness, and fragility fractures. TIO is characterized by hypophosphatemia, excess renal phosphate excretion, and low/inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH) 2 D) levels. Rarity and enigmatic clinical presentation of TIO contribute to limited awareness among the medical community. Accordingly, appropriate diagnostic tests may not be requested, leading to delayed diagnosis and poorer patient outcomes. We have developed a global guidance document to improve the knowledge of TIO in the medical community, enabling the recognition of patients with TIO and appropriate referral. We provide recommendations aiding diagnosis, referral, and treatment, helping promote a global standard of patient management. We reviewed the literature and conducted a three-round Delphi survey of TIO experts. Statements were drafted based on published evidence and expert opinions (≥70% consensus required for final recommendations). Serum phosphate should be measured in patients presenting with chronic muscle pain or weakness, fragility fractures, or bone pain. Physical examination should establish features of myopathy and identify masses that could be causative tumors. Priority laboratory evaluations should include urine/serum phosphate and creatinine to assess renal tubular reabsorption of phosphate and TmP/GFR, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25(OH) 2 D, and FGF23. Patients with the clinical/biochemical suspicion of TIO should be referred to a specialist for diagnosis confirmation, and functional imaging should be used to localize causative tumor(s). Recommended treatment is tumor resection or, with unresectable/unidentifiable tumors, phosphate salts plus active vitamin D, or burosumab., (© 2022 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

A 36-year-old woman was admitted to the Peking Union Medical College Hospital with a history of fractures for 2 years, limb weakness for 1 year, and ostealgia for 2 months. The patient's examination identified iron deficiency anemia, significantly decreased serum calcium and 25-hydroxyvitamin D3 levels, and increased alkaline phosphatase and parathyroid hormone levels. Imaging showed several typical signs of osteomalacia. Considering the history of Roux-en-Y gastric bypass surgery, the diagnosis was considered to be osteomalacia caused by a postoperative nutritional absorption disorder. The patient was supplemented with calcitriol, calcium, and vitamin D and gradually returned to normal physical activity. The bone metabolism indicators and bone density were significantly improved.

Objectives: Pseudohypoparathyroidism (PHP) is a rare disease, especially when combined with pregnancy. We aimed to explore the changes in serum calcium/parathyroid hormone (PTH) level and medical treatment in a case series of PHP during pregnancy and the postpartum period., Methods: A total of five PHP patients with six pregnancies were enrolled. The classification of PHP was based on (epi)genetic analysis. Clinical characteristics, biochemical indices, and treatment strategies before, during, and after pregnancy were retrospectively collected., Results: All patients received calcium and vitamin D agents with nearly normal serum calcium before pregnancy except patient 2 who was found hypocalcemic during gestation. All patients chose Cesarean section, and one suffered preterm delivery due to oligoamnios. The neonatal birth weight ranged from 2,250 to 4,300 g, and all neonates were free of hypocalcemia-related symptoms. The change in calcium metabolism was inconsistent including stable, improved, or worsened during pregnancy. Serum PTH level remained low in the first two trimesters in patients with stable and improved conditions while increased in the last two trimesters in patients with a worsened condition. Serum calcium changed inconsistently while PTH increased consistently during lactation. For patients who did not breastfeed, calcium homeostasis improved after delivery., Conclusion: Calcium homeostasis and medicine dosage changed differently in PHP patients during pregnancy and lactation. However, most patients had good pregnancy outcomes. Serum PTH levels might predict changes in calcium metabolism during pregnancy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Yang, Wang, Song, Jiang, Li, Xia, Liu, Wang and Xing.)

Objective: Osteoblasts are discovered to secrete hormones with endocrine effects on metabolism, and osteocalcin (OC) is the most abundant non-collagenous protein in bone. We investigate the relationship between serum OC levels and glycolipid metabolism and muscle function in children with osteogenesis imperfecta (OI)., Methods: A total of 225 children with OI and 80 healthy controls matched in age and gender were included in this single center study. Serum levels of fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), low- and high-density lipoprotein cholesterol (LDL-C, HDL-C) were measured by automated analyzers. Serum levels of fasting insulin (FINS) were measured using an automated electrochemiluminescence system. Serum levels of OC and undercarboxylated osteocalcin (ucOC) were measured by enzyme-linked immunosorbent assay. Grip strength and timed-up-and-go (TUG) test were measured. Bone mineral density (BMD) and body composition were measured using dual-energy X-ray absorptiometry., Results: OI patients had significantly higher body mass index (BMI), FBG, and HOMA-IR, but lower HDL-C levels, lower grip strength and longer TUG than control group (all P <0.05). Serum OC, ucOC levels, and ucOC/OC in OI type III patients were significantly lower than those in OI patients with type I and IV. Serum levels of OC, ucOC, and ucOC/OC were negatively correlated to BMI, FBG, insulin levels, and HOMA-IR (all P <0.05). The ratio of ucOC/OC was positively correlated to grip strength (r=0.512, P =0.036), lean mass percentage (%LM) of the total body and limbs, and negatively correlated to fat mass percentage (%FM) of the total body, %FM and fat mass index (FMI) of the trunk (all P <0.05)., Conclusions: Obesity, glucolipid metabolic abnormalities, and reduced grip strength were common in children with OI. Circulating osteocalcin and ucOC may play an important role in the regulation of glucose metabolism, as well as the muscle function of children with OI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zheng, Hu, Zhao, Zhou, Wang, Jiang, Xia, Xing and Li.)

Hyperplastic callus (HPC) is the most conspicuous features of osteogenesis imperfecta (OI) type V, of which accurate diagnosis and treatment are facing challenges. We investigate the clinical features, and impact factors of HPC in OI type V patients. In this retrospective single-center study, a total of 21 patients with type V OI confirmed by IFITM5 mutation were included. Radiological characteristics of bone were evaluated by X-rays, dual-energy X-ray absorptiometry, and computed tomography scan. Bone biopsy specimens were performed and stained by routine hematoxylin-eosin. The effects of bisphosphonates on HPC were investigated. Eleven patients (52.3%) had HPCs at 19 skeletal sites, 11 of which affected the femur. Three patients developed four (21.1%) HPCs after fractures, and 15 (78.9%) HPCs occurred in absence of bone fracture. The progress of HPCs was variable, of which most HPCs enlarged in the initial phase and remained stable, and only one HPC dwindled in size. One patient had a rapidly growing mass on the right humerus, and biopsy showed irregular trabeculae of woven bone and immature bone and cartilage in the loose and edematous collagenous network without signs of tumor. Bisphosphonates treatment had no significant effects on HPC of OI patients. HPC is the specific characteristic of OI type V patients, and its location, shape, size, and progression are variable, and the femur is the most frequently involved site. It is very important to make a diagnosis of HPC through detecting IFITM5 mutation and completing pathological diagnosis if necessary. The treatment of HPC is worth further exploration., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Osteoporosis in men has been neglected despite its association with disability and mortality. We evaluated the effect of bisphosphonates (BPs) on bone mineral density (BMD) and bone turnover biomarkers of osteoporotic men with different androgen levels., Methods: This case-control study included 136 osteoporotic men who were divided into normal group (n = 75) and hypogonadism group (n = 61) (patients treated with testosterone were excluded) according to their serum testosterone levels (cutoff value, 350 ng/dL). BMD, serum testosterone, total alkaline phosphatase, and cross-linked C-telopeptide of type I collagen were detected. The relationship between testosterone levels and BMD at baseline was evaluated. All patients were treated with BPs for 2 years. We compared the effects of BPs on BMD and bone turnover biomarkers between the 2 groups., Results: At baseline, there were no significant differences in BMD and bone turnover biomarkers between the 2 groups. Testosterone levels were positively correlated with BMD in the hypogonadism group. After treatment, the lumbar BMD increased by 7.65% ± 1.54% and 7.47% ± 1.88% in normal and hypogonadism groups, respectively (both P < .01 vs baseline) and hip BMD increased without significant differences between the 2 groups. Serum cross-linked C-telopeptide of type I collagen and alkaline phosphatase levels decreased without significant differences between the 2 groups (all P < .01 vs baseline)., Conclusion: Testosterone level is positively correlated with BMD in men with hypogonadism. In osteoporotic men, BPs significantly increase spine and hip BMD and decrease bone resorption. The efficacy of BPs is similar in men with or without hypogonadism., (Copyright © 2021 AACE. Published by Elsevier Inc. All rights reserved.)

Zoledronic acid (ZOL) is a therapy inhibiting bone resorption. In this study, generic ZOL (Yigu®) showed its clinical efficacy consistency with original ZOL (Aclasta®) in Chinese postmenopausal women with osteoporosis. This study provides a practical basis for the application of Yigu® in Chinese population., Introduction: Yigu® has been approved its bioequivalence to Aclasta®. However, the clinical efficacy and safety of Yigu® have not been evaluated yet. Here, we compared the effectiveness and safety between Yigu® and Aclasta® in Chinese postmenopausal women with osteoporosis and assessed the efficacy of intravenous infusion of ZOL., Methods: This was a randomized open-label, active-controlled study in postmenopausal women with osteoporosis of 14 clinical centers in China. Postmenopausal women with osteoporosis were recruited and randomized to receive a single infusion of 5 mg Yigu® or Aclasta®. The primary endpoint was the percentage change in bone mineral density (BMD) at lumbar spine after 12 months of treatment and was assessed for equivalence. The secondary endpoint was the percentage change in BMD at proximal femur after 12 months. Additional secondary endpoints were percentage changes in BMD at the above sites after 6 months of treatment and changes in bone turnover biomarkers during ZOL treatment. Safety was also evaluated and compared between two groups., Results: A total of 458 postmenopausal women with osteoporosis were enrolled (n = 227, Yigu®; n = 231, Aclasta®). The mean percentage change in the BMD had no statistical difference at the lumbar spine (5.32% vs 5.18%), total hip (2.72% vs 2.83%), and femoral neck (2.37% vs 2.81%) between Yigu® and Aclasta® groups after 12 months of treatment. The mean difference of BMD change at the lumbar spine after 12 months between two groups was 0.15% (95% CI: - 0.71 to 1.00, equivalence margin: - 1.5%, 1.5%), demonstrating the treatments were equivalent. Meanwhile, the decreases in the P1NP and β-CTX showed no difference between two groups after 14 days and 6 and 12 months of treatment. As regards the whole sample, BMD significantly increased after 12 months of treatment. Also, serum C-terminal telopeptide of type 1 collagen (β-CTX) and procollagen 1 N-terminal peptide (P1NP) significantly decreased at each visit period. The overall adverse events were comparable and quite well between two groups., Conclusion: Intravenous infusion of zoledronic acid achieved the potent anti-resorptive effects which led to significant increase in BMD of Chinese postmenopausal women with osteoporosis. Yigu® was equivalent to Aclasta® with respect to efficacy and safety., (© 2021. The Author(s).)

Objective: To analyze the clinical characteristics and molecular mechanisms of 5 cases of hypoparathyroidism caused by GATA3 gene mutation. Methods: A total of 5 childhood-onset hypoparathyroidism patients with GATA3 mutation were identified from 198 hypoparathyroidism (aged ≤18 years) from 1975 to 2021 in Peking Union Medical College Hospital. Clinical data and biochemical indices of the 5 patients were collected and analyzed retrospectively. Genetic screening was conducted by targeted next-generation sequencing (T-NGS), and bioinformatics analysis was performed to analyze the underline mechanisms. Results: The medium onset age of hypoparathyroidism of the 5 patients was 0.5 (0.1, 1.3) years old, and the time duration from onset to confirmed diagnosis of hypoparathyroidism and hypoparathyroidism- deafness-renal dysplasia syndrome was (7.0±5.2) years and (15.0±5.4) years, respectively. The clinical manifestations included carpopedal spasm accompanied by seizures (5 cases), basal ganglia calcification (5 cases), cataract (1 case), deafness (4 cases), and renal malformations or absence (2 cases). The blood calcium and blood parathormone(PTH) before treatment was (1.65±0.31) mmol/L and (4.64±2.63) ng/L, respectively. The 5 patients carried different heterozygous mutations in GATA3 gene, which caused nonsense mutations, frameshift mutations and splice site mutations, respectively. All the GATA3 gene mutations of the 5 patients are classified as pathogenic or likely pathogenic by the Clin Var database and American College of Medical Genetics and Genomics(ACMG). Conclusions: Attention should be paid to genetic diseases in patients with childhood-onset hypoparathyroidism. The possibility of hypoparathyroidism-deafness-renal dysplasia syndrome should be considered in hypoparathyroidism patients with hearing loss or renal dysplasia. GATA3 gene screening is highly recommended for the confirmation of the diagnosis.

Background: Hypoparathyroidism (hypo-PT) is rare, and studies on hypo-PT, especially during pregnancy and lactation, are limited., Design and Setting: This was a retrospective study on a relatively large case series in a single center from mainland China., Methods: A total of 19 patients with 25 pregnancies, diagnosed with hypo-PT before pregnancy, were enrolled. Data on clinical characteristics and treatment strategies at onset time and around pregnancy period were collected., Results: During pregnancy, except for 2 patients with missing data, 5 patients with 6 pregnancies (6/23, 26.1%) experienced improved hypo-PT condition, defined as an increased serum calcium level; 4 patients with 4 pregnancies (4/23, 17.4%) experienced worsened hypo-PT condition, defined as a more than 0.2 mmol/L decline in the serum calcium level; and 3 patients with 3 pregnancies (3/23, 13.0%) remained in stable hypo-PT condition. The prevalence of adverse pregnancy outcomes was 30.4% (4/23 for preterm delivery; 3/23 for miscarriage). The serum calcium and 24-hour urine calcium levels significantly increased during lactation compared with pregnancy (2.57 ± 0.34 vs 1.99 ± 0.11 mmol/L, P < 0.001; 12.28 ± 5.41 vs 8.63 ± 3.22 mmol/L, P = 0.013), and 5 patients with 5 lactations (5/12, 41.7%) developed hypercalcemia in the first 2 months after delivery., Conclusions: Female patients with hypo-PT had different changes in calcium homeostasis and a high prevalence of adverse outcomes during pregnancy. Thus, they should be monitored closely to maintain the optimal serum calcium level. Decreasing drug dosage during the lactation period should be considered to avoid hypercalcemia., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Autoimmune polyendocrine syndrome type 1 (APS1) is a hereditary disease caused by mutations in the AIRE gene with both endocrine and non-endocrine organ involvement. The existing data from China are limited, and this study aims to describe the phenotypes and genetic characterization in Chinese APS1 patients. In this single-center, retrospective, observational study, comprehensive endocrine and extra-endocrine manifestations were collected, and genetic analysis in AIRE was conducted in patients with APS1 between the years of 1984 and 2018 at Peking Union Medical College Hospital., Results: In total, 13 patients from 12 unrelated families were enrolled, seven of whom were female, with hypoparathyroidism, chronic mucocutaneous candidiasis, and Addison's disease being the most frequently observed manifestations. Up to 84.7% presented with two or three of the above-mentioned manifestations, and nearly 4.9 ± 1.8 components presented in patients aged 21.2 ± 7.9 years old. Several less common phenotypes, such as myeloproliferative disease, pure red cell aplasia, renal tubular acidosis, asplenia, autoimmune hepatitis, and ankylosing spondylitis, were also observed in patients. Altogether, seven different AIRE mutations were found in six patients, four of which (K161fs, G208V, A246fs, and L308F) had not been previously reported in patients with APS1., Conclusion: We have provided a comprehensive profile of Chinese patients with APS1, with less commonly observed features being observed in addition to more regularly seen manifestations. Additionally, different AIRE mutations that were observed have expanded the genetic spectrum, which will help with future understanding of the molecular pathogenesis of APS1.

Purpose: Tumor-induced osteomalacia (TIO) is an acquired form of hypophosphatemia caused by tumors with excess production of fibroblast growth factor 23 (FGF23). Some reports showed that TIO patients had renal Fanconi syndrome (FS) with unidentified mechanism. In this study, we investigated the association between genetic polymorphisms of phosphate transporters in renal proximal tubules and TIO with FS., Methods: We recruited 30 TIO patients with FS (TIO-FS) as well as 30 TIO patients (TIO-nonFS) without any urine abnormalities matched by age and gender. We collected clinical manifestations and conducted targeted sequencing of SLC34A1, SLC34A3 and XPR1 genes and the association analysis between variants in TIO with FS and phenotypes., Results: TIO-FS group had lower levels of serum phosphate (0.44 ± 0.12 vs. 0.51 ± 0.07 mmol/L, p < 0.05) than TIO-nonFS group. Among the 16 SNPs in SLC34A1, SLC34A3 and XPR1 genes, GG/GC genotypes of rs148196667 in XPR1 and AA/TA genotypes of rs35535797 in SLC34A3 were associated with a reduced susceptibility to have FS. The G allele of rs148196667 in XPR1 decreased the risk of FS. The GGAA haplotype in SLC34A3 and GCT haplotype in XPR1 were associated with a decreased risk for FS., Conclusions: The polymorphisms of XPR1 and SCL34A3 are associated with TIO patients with Fanconi syndrome. It provides novel insight to the relationship of phosphate transportation and general functions of renal proximal tubules.

Objective: To determine the clinical features and genetic characters of patients with chronic enteropathy associated SLCO2A1 gene (CEAS). Methods: Five CEAS patients diagnosed at Peking Union Medical College Hospital from January 2012 to December 2019 were enrolled in this study. The clinical manifestations, laboratory test, radiological and endoscopic findings, gene detections, treatments and prognosis of these patients were reviewed and analyzed. Results: Five male patients presented gastrointestinal symptoms after puberty, including abdominal pain, diarrhea, intermittent melena or hematochezia, incomplete bowel obstruction, anemia, hypoalbuminemia and hypokalemia. The whole gastrointestinal tract except esophagus could be involved, especially the stomach and ileum. Intestinal lesions were characterized by multiple shallow ulcers with stenosis in the layers of mucosa and submucosa. Five patients were all accompanied with primary hypertrophic osteoarthropathy (PHO), and 1 with myelofibrosis and thoracic duct dysplasia. All patients were homozygous or compound heterozygous mutations of SLCO2A1 gene. Conventional treatment of inflammatory bowel disease and COX-2 inhibitors were ineffective. Conclusions: CEAS is an autosomal recessive genetic disease which widely involves the gastrointestinal tract, and can be associated with skin and bone involvement. There is no effective treatment for CEAS at present. CEAS is a different entity from other inflammatory gastrointestinal diseases.

Objective: Duchenne muscular dystrophy (DMD) is a severe X-linked progressive neuromuscular disease that brings a significantly increased risk of osteoporosis and bone fractures. We prospectively evaluated the effects of oral and intravenous bisphosphonates on the bones of children with DMD., Methods: This study included a total of 52 children with DMD. They were divided into zoledronic acid (ZOL), alendronate (ALN), and control groups according to bone mineral density (BMD) and history of fragility fractures. For 2 years, all patients took calcium, vitamin D, and calcitriol. Meanwhile, 17 patients received infusions of ZOL, and 18 patients received ALN. BMD, serum levels of alkaline phosphatase (ALP) and the cross-linked C-telopeptide of type I collagen (β-CTX) were evaluated., Results: After 24 months of treatment, the percentage changes in lumbar spine BMD were 23.2 ± 9.7% and 23.6 ± 8.8% in the ZOL and ALN groups (all P<.01 vs. baseline). The increases did not differ between the ZOL and ALN groups, but were significantly larger than those of the control group (P<.01). Serum β-CTX and ALP levels, respectively, were decreased by 44.4 ± 18.0% and 31.9 ± 26.7% in the ZOL group and by 36.0 ± 20.3% and 25.8 ± 14.4% in the ALN group (all P<.01 vs. baseline)., Conclusion: Zoledronic acid and alendronate had similar protective effects to increase bone mineral density and reduce bone resorption in children with DMD, which were superior to treatment of calcium, vitamin D, and calcitriol., Abbreviations: 25OHD = 25 hydroxyvitamin D; ALN = alendro-nate; ALP = alkaline phosphatase; ALT = alanine aminotransferase; BMD = bone mineral density; BP = bisphosphonate; Ca = calcium; β-CTX = cross-linked C-telopeptide of type I collagen; DMD = Duchenne muscular dystrophy; FN = femoral neck; GC = glucocorticoid; LS = lumbar spine; ZOL = zoledronic acid., (© 2020 American Association of Clinical Endocrinologists. Published by Elsevier, Inc. All rights reserved.)

Objective: To provide more options for preoperative localization diagnosis in patients with primary hyperparathyroidism (PHPT), the diagnostic efficacy of parathyroid 4-dimensional computed tomography (4D-CT) in patients with PHPT was evaluated. Methods: This was a single-center retrospective study including 57 patients with surgical proved PHPT. All of the patients underwent 4D-CT, 99 Tc m -sestamibi parathyroid imaging (MIBI), and ultrasonography (US) preoperatively. The reference standard for correct localization was based on operation reports and pathology confirmation. The patients were grouped according to the preoperative serum calcium levels, tumor diameter, or ectopic lesions (yes/no), respectively. The sensitivity, specificity, positive predictive value, negative predictive value and area under the curve (AUC) of 4D-CT, MIBI and US, alone or in combination, were analyzed in total and each subgroup patients. Results: Fifty-seven patients (39 women, 18 men; mean age of 56.5 years) were evaluated, including four cases with multi-gland disease and thirteen cases with ectopic parathyroid lesions. In all the patients, similar diagnostic efficacy was found in 4D-CT (AUC: 0.943) and MIBI (AUC: 0.927), both of which were higher than that of US (AUC: 0.847) ( P = 0.01 for 4D-CT vs. US; P = 0.04 for MIBI vs. US). In a subset analysis for ectopic quadrants, the diagnostic efficacy of 4D-CT was significantly higher than that of MIBI ( P = 0.04) or US ( P = 0.01), with the sensitivity of 100%, 69.2%, and 61.5%, and AUC of 0.989, 0.846, and 0.808 for 4D-CT, MIBI and US, respectively. Conclusions: 4D-CT has similar diagnostic efficacy for preoperative localization to MIBI in patients with PHPT, and it is superior to MIBI and US in identifying the ectopic parathyroid gland. 4D-CT can be recommended as an alternative preoperative localization method, especially when parathyroid lesions could not be precisely located by US and MIBI.

Autoimmune polyendocrine syndrome type 1 (APS‑1) is a rare inherited autoimmune disease, characterized by a classic triad, including chronic mucocutaneous candidiasis, primary adrenocortical insufficiency and hypoparathyroidism. The present study investigated phenotypes and pathogenic variants in a Chinese woman with non‑classical APS‑1. Disease‑associated variants in a patient with APS‑1 were identified via targeted next generation sequencing and the variant was confirmed via Sanger sequencing. Serum levels of calcium, phosphorus, parathyroid hormone (PTH), follicle‑stimulating hormone (FSH), luteinizing hormone (LH), estradiol and urinary levels of calcium were measured. Blood count assays and bone marrow morphology were investigated. The patient was a 32‑year‑old woman who had suffered from typical carpopedal spasms since she was 7 years old. She developed syncope, primary amenorrhea, intermittent diarrhea and general fatigue in subsequent years. Hypocalcemia, hyperphosphatemia, low levels of PTH and estradiol, elevated levels of FSH and LH, and absence of erythroblasts were observed, which indicated hypoparathyroidism, primary ovarian insufficiency and pure red cell aplasia. A novel heterozygous missense variant (NM&#95;000383.2: c.623G>T, NP&#95;000374.1: p.Gly208Val) in exon 5 of autoimmune regulator and a reported variant (NM&#95;000383.2: c.371C>T, NP&#95;000374.1: p.Pro124Leu) in exon 3 were detected, of which the c.623G>T variant may be a pathogenic variation that induces APS‑1. Under a regular follow‑up and therapeutic adjustment of calcium, calcitriol, hormone replacement therapy and methylprednisolone, the endocrine function and clinical symptoms of the patient were notably improved. The results of the present study expand the known genetic and phenotypical spectra of APS‑1.

Background: Spondyloepiphyseal dysplasia congenita (SEDC) is an extremely rare inherited chondrodysplasia characterized by abnormal epiphyses, short stature, and flattened vertebral bodies. We investigate the phenotypes and the disease-associated variants of SEDC in two unrelated Chinese families., Methods: We identified disease-associated variants in two nonconsanguineous families with SEDC using targeted next-generation sequencing and confirmed the variants using Sanger sequencing. We investigated the phenotypes of the patients, including clinical manifestations, bone turnover biomarkers, bone mineral density and skeletal radiographic features., Results: Two probands were diagnosed as SEDC according to the phenotypes of disproportionately short-trunk stature, kyphosis, lumbar lordosis and adduction deformity of hips. Radiographs revealed kyphosis and lumbar lordosis, flattened vertebral bodies, compressed femoral heads and shortening of the femurs. Bone mineral density of the probands was lower than that of age- and gender-matched normal children, but bone turnover biomarker levels were within normal range. Two novel heterozygous missense variants (NM&#95;001844.5: c.1654 G>A, NP&#95;001835.3: p.Gly552Arg; NM&#95;001844.5: c.3518G>T, NP&#95;001835.3: p.Gly1173Val) in collagen type II alpha 1 chain (COL2A1) were detected in the two families, which would impair the formation of stable triple-helical type II collagen., Conclusions: We identified two novel disease-associated variants in COL2A1, which led to severe SEDC. Our findings expanded the gene variant spectrum and phenotypic spectrum of extremely rare type II collagenopathies., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Objective: To investigate the association of GNA11 gene polymorphisms with the risk of adult-onset non-surgical hypoparathyroidism (Ns-HypoPT). Methods: Genotyping of GNA11 single nucleotide polymorphisms (SNPs) (rs28685098, rs4806907, rs11084997 and rs78003011) was carried out in 203 patients and 209 healthy participants by sequenom MassArray iPLEX System. These SNPs are located in promoter and 3'untranslated region (3'UTR) of GNA11 gene, respectively. Results: Allele and genotype frequencies of rs11084997 in patients were significantly different from those of controls (genotype GG:60.5% vs. 49.8%, GC: 35.5% vs. 41.6%, CC: 4.0% vs. 8.6%, P= 0.038; G allele 78.3% vs. 70.6%, C allele 21.7% vs. 29.4%, P= 0.012), and the C allele of rs11084997 carriers had a lower risk to develops Ns-HypoPT in additive and dominant genetic models [ OR= 0.382 (0.160-0.915), 0.647 (0.437-0.957)]. CC-Haplotype formed by the minor alleles of rs4806907 and rs11084997 was associated with a decreased risk of Ns-HypoPT in additive, dominant and recessive genetic model [ OR= 0.317 (0.126-0.801), 0.640 (0.430-0.952), 0.367 (0.148-0.912)]. Conclusion: The minor allele C of rs11084997 in GNA11 gene promoter was associated with decreased risk of Ns-HypoPT in Chinese population.

Background: Primary hypertrophic osteoarthropathy (PHO) is a rare disease related to HPGD and SLCO2A1 gene mutation. Gastrointestinal involvement of PHO is even rarer with unknown pathogenesis. Clinical features of GI complication in PHO mimics other auto-immune based bowel entities, such as inflammatory bowel diseases and cryptogenic multifocal ulcerous stenosing enteritis (CMUSE). We aimed to analyze the clinical, genetic, radiological and pathological features of Chinese patients with PHO and determine the difference between PHO patients presenting with and without GI involvement., Methods: We reported two PHO cases with gastrointestinal involvement and reviewed all the studies of PHO in Chinese population published from January 1, 2000, to April 30, 2018. Clinical and genetic presentations of PHO in Chinese patients were analyzed. We compared the characteristics of those patients with gastrointestinal involvement against those without., Results: The two patients were both males with complete-form PHO for more than 10 years. GI related symptoms included diarrhea, chronic gastrointestinal hemorrhage, incomplete intestinal obstruction, anemia, and edema, which were unresponsive to etoricoxib treatment. Radiological examinations revealed segmental intestinal stenosis and thickened intestinal wall. Endoscopic findings included multiple ulcers and mucosal inflammation. Both patients had mutations of SLCO2A1 according to sequence analysis. The surgical pathology revealed chronic inflammation involving the intestinal mucosa and submucosa, similar to histological changes in CMUSE. According to the systemic review of 158 Chinese patients with PHO, 17.2% had gastrointestinal involvement, including peptic ulcer, gastric polyps, hypertrophic gastritis, and segmental intestinal stenosis. Patients with gastrointestinal involvement were more likely to have anemia (40.0% vs. 4.5%, P < 0.001), hypoalbuminemia (16.7% vs. 0.9%, P = 0.003), and myelofibrosis (19.0% vs. 0.9%, P = 0.002) than those without. Most patients with gastrointestinal complication had SLCO2A1 mutation (86.7%, 13 /15)., Conclusions: Digestive tract involvement is uncommon in patients with PHO and often presents with anemia, and hypoalbuminemia resulted from intestinal inflammation. The intestinal pathologic characteristics are distinct from Crohn's disease but similar to CMUSE. Mutations in SLCO2A1 might be the pathogenic cause of GI involvement of PHO. NSAIDs may not be effective for PHO patients with gastrointestinal complications.

Background: To introduce the concept of "ring sign" and to evaluate its role in the diagnostic imaging of osteochondromyxoma in patients with Carney complex (CNC)., Methods: Three patients presenting osteochondromyxoma with CNC were included for evaluation of the ring sign on different imaging modalities, including radiographs, computed tomography, and magnetic resonance imaging. The literature was reviewed for further discussion., Results: The ring sign in osteochondromyxoma could be seen on radiographs, computed tomography, and magnetic resonance images in all three patients at each of the involved sites. The morphological patterns and the number of ring signs varied by case, site, and imaging method. Some previous reports have shown images that contain ring signs, but do not identify them as such., Conclusions: Ring sign can be considered as a relatively specific sign, helpful for the imaging diagnosis of osteochondromyxoma in the CNC., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Vertebral compression fracture (VCF) is a common and severe complication of osteogenesis imperfecta (OI). We prospectively observe the changes of vertebral shape during zoledronic acid (ZOL) treatment and assess influence factors of VCF in OI children. 32 children with VCF and 10 children without VCF (NVCF) were included and given ZOL treatment for 2 years, who were matched in age and gender. Control group included 17 treatment naïve OI patients with VCF who were matched in age, gender and clinical severity to 17 patients in VCF group received ZOL treatment for 1 year (as ZOL treated group). We performed quantitative vertebral morphometry and calculated concavity index (mh/ph), height-length ratio (ah/LL, mh/LL, ph/LL) and projection area (PA) of vertebrae from T4 to L4 before and after treatment. At baseline, patients in VCF group had significantly lower PA, mh/ph, ah/LL, mh/LL and ph/LL than patients in NVCF group (P < 0.01). PA, mh/ph, ah/LL, mh/ LL and ph/LL of patients with VCF were raised by (35.2 ± 19.5)%, (22.9 ± 15.1)%, (19.6 ± 13.9)%, (33.6 ± 25.5)%, and (8.1 ± 8.8)% (P < 0.01) after 1-year treatment of ZOL, and were increased by (71.8 ± 28.2)%, (42.8 ± 21.8)%, (35.1 ± 20.6)%, (65.4 ± 43.2)%, and (12.5 ± 11.4)% after 2-year treatment of ZOL (P < 0.01). Compared to control group, mh/ph, ah/LL and mh/LL were significantly higher (P < 0.01) in ZOL treated group. LS-BMD and its increase were positively correlated to vertebral height and PA at baseline and the improvement of vertebral height and PA after ZOL treatment, respectively. In conclusion, the compressive vertebrae of OI children could be effectively reshaped during ZOL treatment. Low LS-BMD was an independent risk factor for VCF and its increase was positively correlated to the improvement in vertebral shape after ZOL treatment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Primary hypertrophic osteoarthropathy (PHO) is an inherited disease characterized by digital clubbing, periostosis and pachydermia with defects in the degradation of prostaglandin E2 (PGE2). Mutations in SLCO2A1 gene-encoding prostaglandin transporter (PGT) resulted in PHO, autosomal recessive 2 (PHOAR2). The spectrum of mutations and variable clinical complications of PHOAR2 has been delineated. In this study, we investigated a Chinese PHO family with a manifestation of Bartter-like hypokalemia., Methods: Clinical manifestations were collected and genetic analyses were performed in the PHO family., Results: The 33-year-old male proband had severe hypokalemia due to potassium loss from the kidney, while his brother had mild hypokalemia. After being treated with etoricoxib, the serum potassium level of the patient increased rapidly to the normal range which corresponded with the reduction in his serum PGE2 and PE2 metabolite (PGEM) levels. A novel SLCO2A1 compound heterozygous mutation of p.I284V and p.C459R was identified in two PHO patients in this family., Conclusions: The present findings supported that the Bartter-like hypokalemia is a new complication of PHOAR2 caused by the high level of PGE2. Etoricoxib was demonstrated to be effective for the renal hypokalemia in PHO patients.

Background: Osteogenesis imperfecta (OI) is a group of hereditary disorders characterized by low bone mass and recurrent fractures. OI patients of autosomal recessive inheritance are extremely rare, of which OI type XIII is attributable to mutation in BMP1 gene., Case Report: Here, we detect the pathogenic mutations and analyze their relation to the phenotypes in a Chinese family with OI using next-generation sequencing (NGS) and Sanger sequencing. We also evaluate the efficacy of alendronate treatment in the patient with OI type XIII. The clinical phenotypes of the patient included recurrent fractures, muscle weakness, bone deformity, macrocephaly and elbow contractures, but no blue sclera or dentinogenesis imperfecta. High-resolution peripheral quantitative computed tomography revealed high bone mineral density and bone volume, but reduced trabecular numbers, increased porosity and comprised strength in this patient. Novel heterozygous mutations of c.1324G > T (p.Asp442Tyr) and c.148 + 1G > A in BMP1 gene were found in the proband, which would affect the CUB2 domain and the prodomain of mutant proteins. The parents were heterozygous carriers for the two mutations respectively, but with normal phenotype., Conclusions: We report for the first time that the novel pathogenic mutations in BMP1 can lead to the extremely rare OI type XIII, which exhibit unique characters of high bone mass, but with impaired bone microstructure and comprised bone strength. Alendronate is beneficial in increasing bone mineral density and decreasing bone resorption biomarkers, but concerns still remain whether it can reduce fracture incidence in this rare type of OI., (Copyright © 2018. Published by Elsevier B.V.)

Background: Osteogenesis imperfecta (OI), a heritable bone fragility disorder, is mainly caused by mutations in COL1A1 gene encoding α1 chain of type I collagen. This study aimed to investigate the COL1A1 mutation spectrum and quantitatively assess the genotype-phenotype relationship in a large cohort of Chinese patients with OI., Methods: A total of 161 patients who were diagnosed as OI in Department of Endocrinology of Peking Union Medical College Hospital from January 2010 to December 2017 were included in the study. The COL1A1 mutation spectrum was identified by next generation sequencing and confirmed by Sanger sequencing. A new clinical scoring system was developed to quantitatively assess the clinical severity of OI and the genotype-phenotype relationship was analyzed. The independent sample t-test, analysis of variance, Mann-Whitney U-test, Chi-squared test, Pearson correlation, and multiple linear regression were applied for statistical analyses., Results: Among 161 patients with OI, 32.9% missense mutations, 16.8% non-sense mutations, 24.2% splice-site mutations, 24.8% frameshift mutations, and 1.2% whole-gene deletions were identified, of which 38 variations were novel. These mutations led to 53 patients carrying qualitative defects and 67 patients carrying quantitative defects in type I collagen. Compared to patients with quantitative mutations, patients with qualitative mutations had lower alkaline phosphatase level (296 [132, 346] U/L vs. 218 [136, 284] U/L, P = 0.009) and higher clinical score (12.2 ± 5.3 vs. 7.4 ± 2.4, P < 0.001), denoting more severe phenotypes including shorter stature, lower bone mineral density, higher fracture frequency, more bone deformity, vertebral compressive fractures, limited movement, and dentinogenesis imperfecta (DI). Patients would not present with DI if the glycine substitutions happened before the 79th amino acid in triple helix of α1 chains., Conclusions: This presented distinctive COL1A1 mutation spectrum in a large cohort of Chinese patients with OI. This new quantitative analysis of genotype-phenotype correlation would be helpful to predict the prognosis of OI and genetic counseling.

Pregnancy- and lactation-associated osteoporosis (PLO) is a rare disorder with poorly known etiology, pathophysiology, and therapy. We aimed to investigate the clinical characteristics of PLO and evaluate the effectiveness and safety of bisphosphonates on it. A total of 12 patients were diagnosed with PLO on the basis of medical history, bone mineral density (BMD), and/or fragility fractures during pregnancy and lactation. We investigated the clinical, biochemical, and radiological characteristics of patients. We assessed the effects of alendronate or zoledronic acid through observing the changes of bone turnover biomarkers and BMD during the treatment. Secondary osteoporosis was excluded by comprehensive differential diagnosis. The mean age of these patients was 31 ± 5 years old. All of these patients presented severe back pain. Multiple vertebral compression fractures (VCFs) were found in 10 patients, and the median (P25th, P75th) number of compressed vertebra was 3 (3, 5). Ten patients had vitamin D insufficiency or deficiency. Serum level of bone resorption marker (β-CTX with mean of 0.68 ± 0.41 ng/ml) was moderately higher than the normal range. BMD at lumbar spine, femoral neck, and total hip were low as 0.894 ± 0.153 g/cm 2 , 0.728 ± 0.090 g/cm 2 , and 0.728 ± 0.080 g/cm 2 , respectively. Either alendronate or zoledronic acid could effectively relieve bone pain, reduce β-CTX level, and increase BMD. PLO is a rare type of osteoporosis, which was characterized by increased bone resorption and decreased BMD, even VCFs. Bisphosphonate therapy was well tolerated and effective in management of PLO, but needed to be further verified in randomized controlled trial.

Background: Primary hypertrophic osteoarthropathy (PHO) is a rare disease involving joint, bone and skin. Two underlying genes responsible for this disease-hydroxyprostaglandin dehydrogenase ( HPGD ) and solute carrier organic anion transporter family, member 2A1 ( SLCO2A1 )-are both associated with aberrant accumulation of prostaglandin E2 (PGE2). Cyclooxygenase-2 (COX-2) is a key enzyme in PGE2 synthesis. This study was intended to evaluate the safety and efficacy of COX-2 inhibitor in the treatment of PHO., Methods: We recruited patients presenting to Peking Union Medical Hospital between January 2009 and December 2016 who were diagnosed with PHO. Participants were given the COX-2 inhibitor etoricoxib (60 mg once daily) and followed up for 9 months. Gene analysis was performed at baseline. The following data were collected at baseline and during treatment: visual analogue score (VAS), volume of the distal middle finger (VDMF), knee joint circumference (KJC), serum and urinary levels of prostaglandin E2 (PGE2) and PGE metabolite (PGE-M) and serum levels of inflammatory markers., Results: A total of 27 patients were recruited, including seven patients with PHO type I (PHOAR1) carrying HPGD gene mutations and 20 patients with PHO type II (PHOAR2) carrying SLCO2A1 gene mutations. After treatment with etoricoxib, the majority of patients experienced resolution of symptoms including pachydermia (60.9%), joint swelling (100%), digital clubbing (74.1%) and hyperhidrosis (55.0%). In both the PHO subtypes, serum and urinary levels of PGE2 were elevated at baseline and declined sharply upon treatment. For PHOAR1 patients, serum and urinary PGE-M levels were relatively low and demonstrated minimal response to COX-2 inhibition. Among PHOAR2 patients, mean serum and urinary levels of PGE-M presented at a high level at baseline and were normalized after 3 months of treatment. No severe adverse effects were reported during the study period., Conclusions: We found COX-2 inhibitor to be safe and effective for the treatment of PHO in our cohort., The Translational Potential of This Article: The underlying genes responsible for PHO suggest COX inhibitor as potential therapy, and our study demonstrates the efficacy and safety of this treatment.

Background: Elevated triglyceride to high density lipoprotein cholesterol (TG/HDL-C) ratio has been identified as a surrogate marker of insulin resistance and an independent predictor for cardiovascular events in the general population. However, the prognostic value of TG/HDL-C ratio in revascularized ST-elevation myocardial infarction(STEMI) patients remains unclear. We examined the association between TG/HDL-C ratio and clinical outcome of revascularized STEMI patients in the Chinese population., Methods: 464 STEMI patients who underwent successful revascularization were enrolled to determine the relationship between TG/HDL-C ratio and major adverse coronary events(MACEs) with a 30-month follow-up. The Kaplan-Meier analysis and Cox regression proportional hazard model were applied to assess the prognostic value of TG/HDL-C ratio., Results: TG/HDL-C ratio was found to be significantly associated with age (p = 0.017), history of diabetes(p = 0.017), heart rate(p = 0.011), TG(p < 0.001), HDL-C(p < 0.001) and Gensini score(p = 0.034). The multivariate Cox regression analysis revealed that elevated TG/HDL-C ratio was an independent prognostic factor for MACE in female patients (HR = 2.624,95%CI = 1.211-5.687,p = 0.014) but not in male patients(HR = 0.756, 95%CI = 0.484-1.179,p = NS) after adjustment with other MACE-related prognostic factors., Conclusion: The TG/HDL-C ratio may be independently associated with MACEs in female revascularized STEMI patients in the Chinese population., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The care of individual patients requiring anthracyclines remains challenging as uncertainty persists on predictors of cardiotoxicity. The aim of the present study was to identify potential candidate blood indicators of doxorubicin-induced heart failure. The gene expression profiles of GSE40447 and GSE9128 microarray data were downloaded from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) using the R/Limma package or GEO2R. Functional and pathway enrichment analysis on DEGs were performed using DAVID database. The cardiovascular disease (CVD)-related DEGs were screen out based on the CardioGenBase database. The protein-protein interaction (PPI) network was constructed with STRING database and visualized by using Cytoscape. Then, the CVD-related DEGs were validated by intersection analysis with DEGs in GSE9128. The overlapping DEGs with a consistent expression pattern in GSE40447 and GSE9128 were identified as candidate indicators for doxorubicin-induced heart failure. A total of 516 DEGs potentially associated with doxorubicin-induced heart failure in GSE40447 were identified, which were mainly enriched in the gene ontology terms related to B cells, leukocytes, lymphocyte activation and B cell receptor signaling pathway. Of the DEGs, 42 were screened out as CVD-related DEGs by using CardioGenBase. Seven genes with high connectivity degree were presented in the PPI network. Finally, 5/6 CVD-related DEGs revealed by the intersection analysis were validated by GSE9128 and highlighted as candidate indicators of doxorubicin-induced heart failure: CD163, CD28, SLC25A20, ANPEP and TLR5. Several genes, including the 5 previously mentioned, were proposed as potential candidate blood indicators for doxorubicin-induced heart failure. Further experimental validations are greatly warranted for future clinical application.

Baseline and on-treatment characteristics, including age, obesity, calcium intake, and bone turnover markers, may predict the bone mineral density (BMD) response in women with postmenopausal osteoporosis (PMO) to 1 to 2 years of antiresorptive therapy and/or vitamin D supplementation. This study aimed to explore clinical characteristics associated with 12-month BMD improvement in Chinese women with postmenopausal osteoporosis (PMO).In this post hoc analysis of a previous phase 3 multicenter, randomized controlled trial, Chinese PMO women who were treated with once weekly alendronate 70 mg/vitamin D3 5600 IU (ALN/D5600) or once daily calcitriol 0.25 mcg, and had measurements of 1-year lumbar spine BMD (LS-BMD) and on-treatment bone turnover markers (BTMs) were included in the analysis.In Chinese PMO patients on ALN/D5600, 1-year LS-BMD change was negatively correlated with age (β = -0.00084, P < .01), dietary calcium (β = -0.0017, P = .07), and procollagen type 1 N-terminal propeptide (P1NP) change at month 6 (β = -0.000469, P = .0016), but positively with body mass index (BMI) (β = 0.00128, P = .08); baseline P1NP above the median was associated with a significantly greater BMD percentage change at the lumbar spine (P = .02) and the total hip (P = .0001). In the calcitriol group, a significant 1-year LS-BMD increase was associated with BMI (β = 0.0023, P = .02), baseline P1NP (β = 0.00035, P = .0067), history of prior vertebral fracture(s) (β = 0.034, P < .0001) and baseline serum 25(OH)D level (β = -0.00083, P = .02).The presented findings from Chinese postmenopausal osteoporotic women suggested clinically meaningful baseline and on-treatment characteristics predicting BMD improvement after 1 year of ALN/D5600 treatment, which differed from calcitriol treatment with baseline identifiable associations. The study remained exploratory and further accumulation of evidence is needed.

Atomic clocks based on laser-cooled atoms are widely used as primary frequency standards. Deploying such cold atom clocks (CACs) in space is foreseen to have many applications. Here we present tests of a CAC operating in space. In orbital microgravity, the atoms are cooled, trapped, launched, and finally detected after being interrogated by a microwave field using the Ramsey method. Perturbing influences from the orbital environment on the atoms such as varying magnetic fields and the passage of the spacecraft through Earth's radiation belt are also controlled and mitigated. With appropriate parameters settings, closed-loop locking of the CAC is realized in orbit and an estimated short-term frequency stability close to 3.0 × 10 -13 τ -1/2 has been attained. The demonstration of the long-term operation of cold atom clock in orbit opens possibility on the applications of space-based cold atom sensors.

Background: Vitamin D (VD) insufficiency or deficiency is a frequent comorbidity in Chinese women with postmenopausal osteoporosis (PMO). The present study aimed to investigate 25-hydroxyvitamin D [25(OH) D] improvement and calcium-phosphate metabolism in Chinese PMO patients treated with 70 mg of alendronate sodium and 5600 IU of vitamin D 3 (ALN/D5600)., Methods: Chinese PMO women (n = 219) were treated with 12-month ALN/D5600 (n = 111) or calcitriol (n = 108). Changes in 25(OH) D at month 12 were post hoc analyzed by the baseline 25 (OH) D status using the longitudinal analysis. The main safety outcome measures included serum calcium and phosphate and 24-h urine calcium, and the repeated measures mixed model was used to assess the frequencies of the calcium-phosphate metabolic disorders., Results: Absolute change in mean serum 25(OH) D level was the greatest in VD-deficient patients and least in VD-sufficient patients at months six and 12 (both, P < 0.01). Serum calcium level remained significantly lower in the ALN/D5600 treatment group than in the calcitriol treatment group throughout the 12 months. Mean 24-h urine calcium slightly increased in the ALN/D5600 treatment group and significantly increased in the calcitriol treatment group (+ 1.1 and + 0.9 mmol/L at months six and 12; both, P < 0.05). Calcitriol treatment was associated with more frequent hypercalciuria at month six (9.4% vs. 18.5%, P = 0.05), but not at month 12 (12.3% vs. 13.0%)., Conclusion: Baseline VD status predicted 25(OH) D improvement in PMO patients on 12-month ALN/D5600 treatment. The daily use of 0.25 μg of calcitriol was associated with more frequent hypercalciuria at month six, compared to ALN/5600 treatment, necessitating the safety re-evaluation of calcitriol at a higher dosage.

Objective: To study the clinicopathological characteristics and immunohistochemical phenotype of phosphaturic mesenchymal tumor (PMT) . Methods: The clinicopathological data and immunohistochemical profiles were obtained retrospectively from 206 patients diagnosed with PMT at Peking Union Medical College Hospital (PUMCH) during July 2008 to September 2017, with a review of literature. Results: The mean age of PMT patients was 42 years (range 13 to 70 years), with a male to female ratio of 1.1∶1.0. All patients presented with different degree of bone pain, muscle weakness, shorten of stature, thoracic deformity and pathological fractures, with hypophosphatemia and high serum ALP. Phosphatemia returned to normal within 1 week after operation in all cases underwent complete tumor resection. The duration of osteomalacia before resection (documented in 197 cases) ranged from 20 days to 40 years (average 5.7 years). The average blood phosphorus concentration raised from 0.49 mmol/L to 0.92 mmol/L before and after tumor resection ( P <0.01), with 147 cases (84.0%, 147/175) returned to normal range within 2 weeks. The rate or blood phosphorus concentration recovery in 15 days after operation was 79.6% in average, displayed significant differences between patients with complete resection and those with partial resection (85.4% vs. 21.1%, P <0.01). PMT lesions mainly involved lower extremities (55.8%), followed by head and neck (29.1%). In immunohistochemical study, all cases were positive for vimentin (100.0%), while most cases were positive for NSE (96.3%), CD56 (94.2%), FGF23(88.4%), CD68 (88.3%), D2-40 (70.9%), CD34 (23.1%), SMA (55.5%), bcl-2 (59.8%) and CD99 (47.1%). The Ki-67 positive index of tumor varied from less than 2% (51.4%), 3% to 10% (41.3%) to >10% (7.2%). Conclusions: PMT mainly occurs in lower limbs or head and neck, with unique clinical characteristics and blood biochemical indexes. The tumor expresses a variety of immunohistochemical markers, indicating the potential of multi-directional differentiation. Clinical profile, blood biochemistry testing and immunohistochemical phenotype is helpful for diagnosis of PMT.

Objective: To explore the association between α-actinin-3 ( ACTN 3) polymorphism and muscle strength in postmenopausal women. Methods: Five hundred and ninety-eight postmenopausal women with an average of (62.9±7.0) years old in Dongcheng District of Beijing were included. The ACTN 3 polymorphism including rs540874, rs618838 and rs2229456 were genotyped by Sequenom Mass Array to explore their associations with muscle strength. One hundred and sixty-three of them were trained with regular Tai chi movement while 271 were administered with elemental calcium 600 mg/d combined with Vitamin D 800 U/d or calcitriol 0.25 μg/d for 2 years. Association between changes of muscle strength and ACTN 3 polymorphism were analyzed. Results: The rs540874 genotypes were found to be significantly associated with chair stand test[GG (9.02±3.85) s vs GA (9.27±4.14) s vs AA (9.68±5.00) s, P =0.015]. Right grip strength in women with G allele were likely to be higher compared with A allele, but it was not statistically significant ( P =0.056). Multiple linear regression showed that the chair stand test of AA genotype was statistically longer than that of GG and GA genotype (β=2.639, 95% CI : 1.632-4.646, P =0.010). The associations between rs618838, rs2229456 genotypes and muscle strength of both lower and upper limbs were not significant (all P >0.05). In addition, muscle strength of lower limbs of patients with rs540874 genotyped with G allele, rs618838 genotyped with C allele and rs2229456 genotyped with A allele increased significantly after enhanced exercise and vitamin D supplementation (all P <0.05). Conclusions: The rs540874 polymorphism of ACTN 3 gene was associated with the muscle function of lower limb in postmenopausal women. The improvement of muscle strength after intervention were possibly correlated with rs540874, rs618838 and rs2229456 polymorphisms.

Backgrounds: SERPINF1 mutations caused deficiency of pigment epithelium-derived factor (PEDF) and would lead to osteogenesis imperfecta (OI) type VI. However, serum PEDF levels were unclear in Chinese OI patients who had clear molecular diagnosis., Objective: To assess PEDF levels in different genotypes of OI, to evaluate the influencing factors of PEDF in Chinese OI patients with clear molecular diagnosis., Methods: Known candidate genes of OI were examined by a targeted next generation sequence. Serum PEDF levels were measured by ELISA in 6 OI patients with SERPINF1 mutations, 6 carriers of one copy of the SERPINF1 mutation, 88 OI patients with COL1A1, CLO1A2, IFITM5 and other pathogenic mutations of OI and 24 healthy controls. We compared the differences in serum PEDF levels among different OI patients and normal controls., Results: Serum PEDF levels were extremely low in OI patients with SERPINF1 mutations (0.66±1.60μg/ml) than in OI patients with other pathogenic mutations (4.88±1.43-7.07±2.43μg/ml), carriers of one copy of SERPINF1 mutation (4.94±2.35μg/ml), and normal controls (7.29±2.31μg/m) (P<0.001). No significant differences in serum PEDF concentrations were found among patients with OI type I, III or IV, and between patients with or without bisphosphonate treatment. Serum PEDF level was positively correlated with Z-score of weight (r=0.310, P=0.004), BMI (r=0.253, P=0.020) and alanine aminotransferase (r=0.291, P=0.007)., Conclusions: Extremely low level of PEDF was demonstrated as a specific, convenient, and inexpensive diagnostic biomarker for OI patients with SERPINF1 mutations, but it could not provide information regarding the clinical severity of OI and the efficacy of bisphosphonates treatment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To investigate the glucose and lipid metabolic disorders in patients with myasthenia gravis (MG) without glucocorticoid therapy, and the relationships between insulin, insulin resistance, muscle strength, serum levels of osteocalcin, 25-hydroxy vitamin D (25OHD) and glucose and lipid metabolism. Methods: A total of 102 MG patients [(40±11) years old, 43 males and 59 females] without glucocorticoid treatment were enrolled in this cross-sectional study. Height, weight and the handgrip of dominant hands were measured. Serum levels of fasting blood glucose (FBG), 2-hour postprandial blood glucose (2 h PBG), glycosylated hemoglobin (HbA1c), fasting insulin (FINS), 2-hour postprandial insulin (2 h PINS), total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and osteocalcin, 25OHD were detected. Insulin resistance was assessed using homeostasis model assessment of insulin resistance (HOMA-IR). Results: The proportion of impaired fasting glucose or impaired glucose tolerance, type 2 diabetes, dyslipidemia, hyperinsulinemia in male and female were 30.0%, 10.0%, 50.0%, 33.3% and 17.5%, 3.5%, 27.7%, 7.1%, respectively. Serum osteocalcin levels in male and female were 2.8 (1.7, 4.4) μg/L and 2.3 (1.3, 3.9) μg/L, respectively. And 25OHD levels in male and female were (93.5±34.9) nmol/L and (81.0±30.5) nmol/L, respectively. Handgrip of male and female was (37.0±9.4) kg and (20.5±6.3) kg. After adjusted for age, FINS ( r =0.619, P <0.001), 2 h PINS ( r =0.640, P <0.001), HOMA-IR ( r =0.534, P <0.001) were positively correlated with 2 h PBG, and the handgrip was negatively correlated with TC ( r =-0.486, P =0.026), LDL-C ( r =-0.485, P =0.026) in male. FINS ( r =0.352, P =0.008; r =0.300, P =0.026; r =0.646, P <0.001) and 2 h PINS ( r =0.278, P =0.040; r =0.518, P <0.001; r =0.382, P =0.006) and HOMA-IR ( r =0.695, P <0.001; r =0.583, P <0.001; r =0.818, P <0.001) were positively correlated with FBG, 2 h PBG, HbA1c, and the handgrip were negatively correlated with FBG ( r =-0.424, P =0.016), 2 h PINS ( r =-0.345, P =0.034) and positively correlated with HDL-C ( r =0.389, P =0.037) in female. There was no association between osteocalcin, 25OHD and glucose and lipid metabolism. Multivariate linear regression analysis also found that there were significant relationships between handgrip, insulin, insulin resistance levels and glucose and lipid metabolic disorders. Conclusion: There was a high proportion of glucose and lipid metabolic disorders in MG patients without glucocorticoid treatment, and the mechanism may be related to insulin resistance induced by muscle weakness.

Bartter syndrome (BS) is a hereditary condition transmitted as an autosomal recessive (Bartter type 1 to 4) or dominant trait (Bartter type 5). The disease associates hypokalemic alkalosis with varying degrees of hypercalciuria. Here we presented a case (BS type Ⅱ) of a 17 years old female presented with polyhydramnios, polyuria, nephrocalcinosis and hypokalemia, which was alleviated after treatment with celecoxib and vitamin D(3). DNA sequencing identified compound heterozygous KCNJ 1 gene mutations, c. 931C >T (p.R311W) and c. 445-446insCCTGAACAC (p.V149Afs, 150X), with the latter a novel mutation. Her father and mother were heterozygous carriers of c. 931C >T (p.R311W) and c. 445-446insCCTGAACAC (p.V149Afs, 150X), respectively. In conclusion, this case of BS type Ⅱ is caused by a novel compound heterozygous KCNJ 1 mutation. Further studies are needed to verify the effect of celecoxib in BS patients.

Objective: To explore the association of vitamin D receptor ( VDR ) gene polymorphisms with idiopathic hypoparathyroidism (IHP). Methods: Two hundred and three patients with IHP and 209 healthy age- and sex-matched subjects were recruited at Peking Union Medical College Hospital between December 1987 and December 2015 as case group and control group, respectively. The VDR gene polymorphisms including rs739837, rs3847987 and rs2228570 were analyzed by Sequenom Mass Array. The frequency of different genotypes and alleles was detected, then their association with pathogenesis of IHP was analyzed. The clinical characteristics, biochemical indicators were collected to explore the genotype-phenotype relationship. The role of reactions to vitamin D treatment were compared between patients with different genotypes. Results: There was no significant difference in the genotypes and allele frequency distribution of SNPs between the two groups (all P >0.05). However, in the initially-treated patients, the genotypes of rs739837 were related to serum calcium level ( r =0.186, P =0.026). And patients with GG genotype of rs2228750 had higher level of urine calcium than GA and AA (277.7 mg vs 141.1 mg, P =0.024) after treating with oral vitamin D(3) and calcium. Conclusions: Functional SNPs of VDR gene including rs739837, rs3847987 and rs2228570 might be irrelevant to the pathogenesis of IHP. But the genotypes of rs739837 were related to serum calcium level, and rs2228570 may have an effect on the different responses to vitamin D and its analogues in IHP patients.

Diagnostic delay of tumor induced osteomalacia (TIO) is common in clinic practice. To investigate the diagnostic condition of TIO in China and raise clinicians' awareness of TIO, we retrospectively analyzed clinical manifestations, biochemical features, and specially evaluated missed diagnoses and misdiagnoses among 144 TIO patients from Peking Union Medical College Hospital during December 1982 to December 2014. Clinical presentations of TIO mainly included bone pain, difficulty in walking, pathological fractures, muscle weakness, and height loss. TIO patients demonstrated hypophosphatemia (0.48±0.13 mmol/L), elevated serum alkaline phosphatase (277.9±152.6 U/L), reduced tubular maximum for phosphorus/glomerular filtration rate (0.39±0.14) and markedly elevated serum fibroblast growth factor 23 (FGF23) (median level 302.9 pg/mL). The average time from onset to a correct diagnosis was 2.9±2.3 years while the mean duration from onset to tumor resection was 5.4±4.2 years. The initial misdiagnosis rate was 95.1% (137/144) and 240 case-times of misdiagnoses occurred among the 144 cases. The most frequent misdiagnoses were intervertebral disc herniation, spondyloarthritis (including ankylosing spondylitis) and osteoporosis. A total of 43.1% (62/144) cases with hypophosphatemia presented on their laboratory sheets were neglected and missed diagnosed. Our study showed that TIO was frequently misdiagnosed and missed diagnosed due to its rarity, insidious onset, nonspecific clinical manifestations and clinicians' poor recognition. It is necessary to test serum phosphorus in patients with musculoskeletal symptoms and difficulty in walking. The measurement of serum FGF23 is rather valuable. Once hypophosphatemia is discovered, TIO should be suspected and it is highly recommended to search for tumors and perform curative surgery.

Background: Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive autonomic and sensory neuropathy. CIPA is associated with various mutations in NTRK1., Cases: Two unrelated Chinese patients presented separately with symptoms of insensitivity to pain, inability to sweat, repeated painless fractures, and Charcot arthropathy were recruited. Both of them were clinically diagnosed with CIPA. Increased serum bone resorption marker (β-CTX) levels and decreased BMD were observed in both patients. X-ray films revealed enlarged bony calli in the fracture sites, Charcot arthropathy, and bilateral lower limb osteomyelitis. Sanger sequencing demonstrated compound heterozygous mutations in NTRK1 for proband 1 (IVS7-33T>A in intron 7 and c. 2281C>T in exon 17) and for proband 2 (IVS7-33T>A in intron 7 and c.1652delA in exon 14), of which the variation in exon 14 in NTRK1 was a novel mutation., Conclusions: We report the detailed phenotypes, as well as both recurrent and novel mutations in NTRK1 in 2 Chinese patients with CIPA. The genetic findings of our study expand the gene mutation spectrum of CIPA., (Copyright © 2017. Published by Elsevier B.V.)