Misdiagnosed psychiatric manifestations in a rare disease: a case report of secondary anxiety syndrome in Cushing's disease.

Diagnosing and treating secondary psychiatric symptoms with accuracy can be challenging in clinical settings. In this case study, we report on a female patient with Cushing's disease who was misdiagnosed with anxiety disorder during her first psychiatric visit. Following initial ineffective psychiatric intervention, unexplained hypokalemia, and hypothyroidism, the patient visited the endocrinology clinic and was diagnosed with Cushing's disease. During the medical and surgical procedures that followed, high doses of psychotropic medication were continued to treat persisting anxiety. After discharge, the patient developed autonomic dysfunction and impaired consciousness. Upon readmission, serotonin syndrome due to inappropriate psychiatric medication was diagnosed. The management of secondary psychiatric syndromes must be adapted to changes in the patient's primary condition, which necessitates interdisciplinary collaboration in general hospital settings.

Shift in Calcium From Peripheral Bone to Axial Bone After Tumor Resection in Patients With Tumor-Induced Osteomalacia.

CONTEXT: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by excessive production of fibroblast growth factor 23 (FGF23) by a tumor. After successful tumor resection, patients can recover from hypophosphatemia quicky. However, data on the changes in bone mineral density (BMD) and microstructure in the short term after surgery remained unclear. OBJECTIVE: This work aimed to investigate the postoperative changes in BMD and microstructure both in peripheral and axial bone in TIO patients. METHODS: We evaluated BMD and microarchitecture in 22 TIO patients using high-resolution peripheral quantitative computed tomography (HR-pQCT) and dual-energy x-ray absorptiometry (DXA) before and 3 months after surgery in this retrospective study. RESULTS: In this study, a total of 22 TIO patients who had recovered serum phosphate levels postoperatively were enrolled. After surgery, areal BMD (aBMD) increased by 21.6% in the femoral neck, by 18.9% in the total hip, and by 29.5% in the lumbar spine. Moreover, TBS increased by 14.1% (all P < .001). In contrast, trabecular or cortical volumetric BMD (vBMD), and microstructure of trabecular bone (trabecular number, separation and bone volume ratio) and cortical bone (cortical thickness and porosity) at the distal radius or tibia were further deteriorated. Correlation analyses found that changes in femoral neck and total hip aBMD were both conversely associated with changes in trabecular vBMD and bone volume ratio, while positively correlated with change in trabecular separation at the distal radius. CONCLUSION: Although aBMD and microstructure in the axial bone were improved, vBMD and microstructure in the peripheral bone were further impaired shortly after surgery. Correlation of improvement of aBMD in the total hip and femoral neck with deterioration of vBMD and microstructure at the distal radius indicated a shift in calcium from the peripheral bone to the axial bone in the short term after tumor resection in TIO patients.

A Chinese case of CHST3-related skeletal dysplasia and a systematic review.

PURPOSE: We reported a case with carbohydrate sulfotransferase 3 (CHST3) spondyloepiphyseal dysplasia and made a systematic review of all previously reported cases. METHODS: A 14.8-year-old boy underwent clinical, radiological, and genetic evaluations. The patients and five age-matched healthy boys accepted high-resolution peripheral quantitative computed tomography evaluation. All CHST3-related skeletal dysplasia cases from PubMed and Embase were collected and summarized. The genotype-phenotype correlation was analyzed. RESULTS: The proband complained of aggravated joint pain and had a compression fracture of L2 during his second decade. Physical examination showed a height Z score of -4.94, short limbs, and restricted movement of the elbows and knees. X-rays showed carpal epiphyseal dysplasia, enlargement of elbow and knee joints, and subluxation of the left hip. Echocardiography showed abnormal cardiac valves. Compared with the norm, his total and trabecular volumetric bone mineral density (BMD), and the microarchitecture of the trabecular bone had trends to be worse at the distal radius and tibia. Two novel missense variants of c.1343T>G and c.761C>G in CHST3 were inherited from his father and mother, respectively. In the systematic review, short stature, limited joint extension, joint pain, and joint dislocation were the most common characteristics of this disorder. Height Z score and the proportion of hearing impairment had no significant differences between the missense and nonmissense mutations groups. CONCLUSION: Progressive joint pain and movement restriction are the main characteristics of CHST3-related skeletal dysplasia. BMD and bone microarchitecture of this disorder needs further exploration. There is no apparent genotype-phenotype correlation in this disorder.

Ultra-High Performance Liquid Chromatography-Mass Spectrometry-based Serum Metabolomics for Early Diagnosis of Refractory Tumor-induced Osteomalacia: A Case-control Study.

CONTEXT: Nearly 20% patients with tumor-induced osteomalacia (TIO) experienced recurrence or nonrecovery after surgery. Serum fibroblast growth factor 23 and phosphate concentrations are not sufficient for prognosis in such cases. Despite its importance for understanding of prognosis and underlying pathogenesis, the alteration of systemic metabolism in refractory TIO remains unclear. OBJECTIVE: We aimed to find the metabolomic characteristics of refractory TIO and establish a novel predictive model for early discriminating refractory TIO based on their serum metabolomics. DESIGN AND SETTING: Cross-section study for comparison of metabolomic profile between TIO and normal control and longitudinal study for identifying prognostic model. METHODS: Based on liquid chromatography-tandem mass spectrometry, we analyzed the global metabolomes of preoperative sera from 86 samples (32 TIO recovery patients, 11 nonremission patients, and 43 matched controls). Statistical analyses, pathway enrichment, and receiver operating characteristic analysis were performed to identified and evaluate potential markers. RESULTS: Sparse partial least squares discriminant analysis indicated a clear separation of metabolomic profiles between healthy controls (HC) and TIO patients. The serum metabolites altered in different prognostic groups. L-pipecolic acid, 2-dodecylbenzenesulfonic acid, and 2-deoxygalactopyranose were the top 3 metabolites that were significantly perturbed. A combination of L-pipecolic acid and 2-dodecylbenzenesulfonic acid demonstrated a high-performance panel for TIO prognosis evaluated by random forest algorithm (area under the curve = 0.921, 95% CI, 0.787-0.995). CONCLUSIONS: We investigate the global metabolomes of refractory TIO and identify potential prognostic biomarkers preliminarily. A high sensitivity and specificity panel were identified as promising discriminating predictors, which need to be verified in more patients. This work may demonstrate novel insights into TIO prognosis and pathogenesis.

Hyperparathyroidism in a Large Cohort of Chinese Patients With Tumor-induced Osteomalacia.

CONTEXT: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by excessive production of fibroblast growth factor 23 (FGF23) by a tumor. Hyperparathyroidism (HPT) including secondary HPT (SHPT) and tertiary HPT (THPT) in TIO patients, which is believed to be associated with phosphate supplementation, has not been well documented. OBJECTIVES: To clarify the prevalence, clinical characteristics, and risk factors for HPT in a large cohort of Chinese patients with TIO in our hospital. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study enrolled 202 patients with TIO. MAIN OUTCOME MEASUREMENTS: Occurrence of HPT in patients with TIO. RESULTS: HPT was observed in 91 patients (91/202, 45.1%): 84 patients (41.6%) with SHPT and 7 patients (3.5%) with THPT. All patients with THPT underwent parathyroidectomy and only 1 patient experienced recurrence. Compared with patients without HPT, patients with SHPT had longer disease duration, higher rate of phosphate and calcitriol supplementation, lower serum calcium, lower urine calcium excretion, and higher urine phosphate excretion. Compared with patients with SHPT, patients with THPT had even longer disease duration and a higher rate of phosphate and calcitriol supplementation. PTH levels showed positive correlation with intact FGF23 and 1,25-dihydroxyvitamin D levels, but not 25-hydroxy vitamin D level in patients with TIO. Multivariate logistic regression analysis showed that long disease duration and phosphate supplementation were independently associated with occurrence of HPT in patients with TIO. Further logistic regression analysis and restricted cubic spline model revealed dose-response relationship between cumulative dose of phosphate supplementation and PTH levels. CONCLUSIONS: HPT is common in patients with TIO. To avoid the occurrence of HPT in patients with TIO, timely diagnosis and tumor resection is necessary and an excessive dose of phosphate supplementation is not suggested before surgery.

Tumor-induced osteomalacia combined with acromegaly: A case report.

Both acromegaly and tumor-induced osteomalacia (TIO) are rare diseases caused by an excess hormone secreted by neuroendocrine neoplasms, which are growth hormone (GH) and fibroblast growth factor 23 (FGF23), respectively. GH elevates phosphate reabsorption via the effect of insulin-like factor 1 (IGF-1), while FGF23 inhibits phosphate reabsorption and reduces serum phosphate level markedly. A patient who developed a typical acromegaly appearance but was accompanied with height loss and hypophosphatemia for 2 years visited our hospital. Laboratory investigations showed GH and IGF-1 hypersecretion, as well as hypophosphatemia caused by renal phosphate wasting. Magnetic resonance image revealed a pituitary somatotroph adenoma. Octreoscan scintigraphy also found a causative tumor on the right foot for hypophosphatemia. Then, he underwent resection of the tumor on the right foot. His serum phosphate returned to normal immediately but elevated gradually. Then, we removed the pituitary adenoma of the patient, and the GH and phosphate levels returned to the normal range. Here, we report the first case with acromegaly combined with TIO, the changing process of his phosphate concentration suggests an interesting concurrent effect of excess GH and FGF23 in this rare condition.

Improvement of Bone Health and Initiation of Puberty Development in Camurati-Engelmann Disease With Glucocorticoid and Losartan Treatment: A Case Report and Review of Literature.

Camurati-Engelmann Disease (CED) is a rare sclerosing bone disease, sometimes associated delayed puberty. The treatment effect of glucocorticoid and angiotensin II receptor blocker (ARB) in bone health and puberty development remain unclear. We report a case of an 18-year-old girl who presented for a history of an enlarged head, pain of lower limbs, and no menstrual onset or breast development. Radiographs revealed thickening of skull and cortices in the diaphysis but sparse bone trabeculae in the spine and metaphysis. Sanger sequencing detected a mutation of c. 652C>T (p. R218C) in the gene TGFB1 and confirmed the diagnosis of CED. After treatment of a medium-to-small dosage of prednisone and losartan for 28 months, we observed improvement of bone mass in spine and hip and body fat mass and found initiation of puberty development. By a systemic review of current treatment strategies in patients with CED, we found that most cases reported relief of bone pain with treatment of glucocorticoid or ARB, but none has reported the outcome of hypogonadotropic hypogonadism. We propose that long-term use of glucocorticoid combined with ARB may inhibit the activation of TGFß1 in CED, improve adipogenesis, and thus initiate puberty development and improve the bone mass in spine and hip.

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

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 (p = 0.029), 40.2% lower trabecular fraction (p = 0.020), 40.6% weaker stiffness (p = 0.058), and 42.7% weaker failure load (p = 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.

Avoiding Misdiagnosis and Missed Diagnosis for Appropriately Treating Spinal Osteoid Osteomas: A Single-Center Experience.

OBJECTIVES: To analyze the causes of misdiagnosis and missed diagnosis in spinal osteoid osteoma, and to put forward solutions to improve diagnosis accuracy and treatment efficacy in patients. METHODS: We performed a retrospective cohort study on patients with spinal osteoid osteoma in Beijing Jishuitan Hospital from January 1983 to September 2019. All patients underwent surgery. The outcome measures were the extent of local pain, nocturnal pain, radicular symptoms of extremities after surgery, and reduction or disappearance of lesions on CT after surgery. RESULTS: Thirty-seven patients with spinal osteoid osteoma were recruited in the study. A total of 27% were female, and the mean (SD) age at diagnosis was 21.3 (8.7) years. A total of 87.0% of patients presented with nocturnal pain, and 94.7% of patients were responsive to NSAIDS treatment. The mean (SD) time from the initial onset of symptoms to the final diagnosis was 14.7 (12.5) months. Only four of 37 (10.8%) patients were correctly diagnosed with spinal osteoid osteoma on the first visit to the local hospital. CT is associated with a higher diagnosis rate than X-ray or MRI on the first visit. Surgical navigation was used in 88.9% of patients who underwent curettage resection, and in 10% of patients who underwent en bloc resection. A total of 37 of 37 patients (100%) reported relief of local pain and radicular symptoms of extremities after surgery, and no recurrence of tumors was found during follow-ups. CONCLUSIONS: Spinal CTs are recommended to be performed if osteoid osteoma is suspected based on clinical manifestation, including nocturnal pain and responsiveness to NSAIDS treatment, to avoid misdiagnosis and missed diagnosis of spinal osteoid osteoma.

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

Camurati-Engelmann disease (CED) is a rare autosomal-dominant skeletal dysplasia caused by mutations in the transforming growth factor-ß1 (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).

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

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).

Bone mineral density and bone microarchitecture in a cohort of patients with Erdheim-Chester Disease.

BACKGROUND: Erdheim-Chester Disease (ECD) is a rare type of non-Langerhans histiocytosis. Skeletal structures are affected in over 95% ECD patients. Due to the lack of proper imaging assessment tools, the alteration of bone microarchitecture in ECD has not been well studied. High-resolution peripheral quantitative computed tomography (HR-pQCT) is a newly developed assessment of bone mineral density and bone microarchitecture. METHODS: We performed a cross-sectional study with 13 patients diagnosed with ECD in Peking Union Medical College Hospital between October 2018 and June 2019. The diagnosis of ECD was based on typical pathological findings in the context of appropriate clinical and radiological manifestations. Bone geometry, volumetric bone mineral density and bone microarchitecture of those ECD patients were assessed using HR-pQCT at the non-dominant distal radius and distal tibia. Those HR-pQCT parameters were then compared to an ongoing population-based database of HR-pQCT for Mainland Chinese. RESULTS: As a result, remarkable heterogeneity of osteosclerosis in the HR-pQCT images was found in ECD patients, ranging from apparent normal structure, scattered thickening of trabecula, to homogenous consolidation. In terms of quantitative measurements, total volumetric BMD (383.50 mg/cm3, 1.352 times of normal mean, p = 0.023) of the tibia differed significantly in ECD patients, due to the increased trabecular volumetric BMD (291 mg/cm3, 2.058 times of normal mean, p = 0.003). The increased trabecular volumetric BMD of tibia was associated with remarkably increased number of trabecula (1.7/mm, 1.455 times of normal mean, p = 0.002) and increased thickness of trabecula (0.37 mm, 1.466 times of normal mean, p = 0.003). These differences could be due to the existence of dense bone interposed in the trabecula. CONCLUSION: This study is the first to assess the volumetric bone mineral density and bone microstructure with HR-pQCT in a cohort of ECD patients and indicated that the application of HR-pQCT may help to reveal the nature of bone lesions in the disease.

Primary Pituitary Lymphoma in Immunocompetent Patients: A Report on Two Case Studies and the Review of Literature.

Primary pituitary lymphoma (PPL) represents an extremely rare entity. Here, we have reported two recently identified cases of immunocompetent PPL having diffuse large B-cell lymphoma by surgical biopsy. Both patients had hypopituitarism, with one patient developing right ptosis. In both patients, MRI and FDG-PET/CT depicted sellar mass that extended into the cavernous sinus with the right sphenoid also present in one of the patients. No systemic disease was found in these two patients. Surprisingly, we found that both patients had infiltrative lesions in sphenoid sinus mucosa pathologically, but the sphenoid bones that composed the sellar base were visually intact during the biopsy procedure. Chemotherapy was administered to both patients, where one patient achieved remission at the recent follow-up, whereas the other one did not respond to the treatment. The diagnosis of PPL is usually difficult if solely dependent on history, clinical presentation, biochemical indexes, and radiographic findings. We have also updated and reviewed the epidemiologic features, clinical presentations, pathological characteristics, potential mechanisms, therapeutic orientation, and prognostic advances of PPL. A total of 40 cases (including ours and four pediatric patients), histologically diagnosed, were analyzed in terms of clinical presentation, endocrine abnormality, radiological features, pathology, treatment, and follow-up. Hypopituitarism and headache were the most common presentation of PPL, while diabetes insipidus was reported in 13 patients (43.3%). B cell lymphoma was the most common type of pathology, followed by T-cell and NK/T cell. PPL was more invasive in nature at the suprasellar region (72.5%), cavernous sinus (52.5%), and sphenoidal sinus (27.5%) in 29, 21, and 11 patients, respectively. Pediatric patients with PPL seem to be different compared to their adult counterparts in terms of pathogenesis, clinical presentation, and radiological features. The management of PPL usually follows the treatment protocols for PCNSL but has a poor prognosis compared to the pituitary involvement of systemic lymphoma.

Nonremission and Recurrent Tumor-Induced Osteomalacia: A Retrospective Study.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome. It is curable by excision of the causative tumor. However, a few cases may persist or relapse after tumor resection. We aimed to investigate the rate of these events and related factors. We retrospectively studied TIO patients treated with surgery in a tertiary hospital. TIO was established based on a pathologic examination or the reversion of hypophosphatemia. Refractory TIO patients consisted of those with nonremission or recurrent hypophosphatemia after surgery. A total of 230 patients were confirmed as having TIO. After primary surgery, 26 (11.3%) cases persisted, and 16 (7.0%) cases recurred. The overall refractory rate was 18.3%. The median time of recurrence was 33 months. Compared with patients in the recovery group, patients in the refractory group were more likely to be female (59.5% versus 41.0%, p = .029) and have a lower serum phosphate level (0.44 ± 0.13 versus 0.50 ± 0.11 mmol/L, p = .002). The refractory rate was lowest in head/neck tumors (7.5%) and highest in spine tumors (77.8%). Regarding the tissue involved of tumor location, the refractory rate was higher in tumors involving bone than tumors involving soft tissue (32.7% versus 7.0%, p < .001). The outcomes of malignant tumors were worse than those of benign tumors (p < .001): nonremission rate, 21.4% versus 9.7%; recurrence rate, 28.6% versus 6.5%. In the multivariate regression analysis, female sex, spine tumors, bone tissue-involved tumors, malignancy, and low preoperation serum phosphorus levels were identified as risk factors for refractory outcomes. High preoperative fibroblast growth factor 23 (FGF23) levels were also associated with refractory after adjusting for involving tissue and tumor malignancy. In summary, we are the first to report the rate and clinical characteristics of refractory TIO in a large cohort. For patients with multiple risk factors, especially spine tumors, clinical practitioners should be aware of a poor surgical prognosis. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Distinct features of malignant carotid body tumors and surgical techniques for challengeable lesions: a case series of 11 patients.

PURPOSE: Malignant carotid body tumor (CBT) is a rare disorder with poor prognosis. In this article, we presented the clinical features and surgical management of malignant CBTs at our department, aiming to improve the outcome for treating such lesions. METHODS: A retrospective analysis (2005-2018) of CBT excisions at our institution was performed. About 195 patients with CBTs were identified, among which 11 patients with eleven malignant CBTs were identified and carefully reviewed. Data obtained included demographics, radiological details, intra-operative details, post-operative morbidity, and long-term outcomes. RESULTS: Compared with benign CBTs, malignant CBTs have more advanced Shamblin classification (p < 0.001) and larger tumor size (4.5 ± 2.1 cm vs. 6.7 ± 2.6 cm, p = 0.003). Among the 11 malignant cases, 9 patients underwent surgical resection and 8 cases (8/9, 89%) underwent internal carotid artery (ICA) reconstruction. Intra-operative findings showed that malignant CBTs revealed more severe arterial and nerve adhesions. With the use of specific techniques including pre-reconstruction technique and carotid shunt, all surgeries were successful and no deaths or major complications including stroke or hemiplegia occurred perioperatively and during the follow-up. During the follow-up period (41.6 ± 44.5 months), two patients developed distant metastasis at 7 and 11 years post-operatively. The 5-year and 10-year distant metastasis-free survival rates were 72.7% and 36.4%, respectively. CONCLUSIONS: With more advanced Shamblin classification and larger tumor size, malignant CBTs remain challengeable for surgery due to severe intra-operative hemorrhage, need of vascular reconstruction and cervical nerve injury. Specific surgical techniques including pre-reconstruction technique and carotid shunt are safe and effective to improve the outcome.

Comparative analysis of the two extremes of FLNB-mutated autosomal dominant disease spectrum: from clinical phenotypes to cellular and molecular findings.

Non-randomly distributed missense mutations of Filamin B (FLNB) can lead to a spectrum of autosomal dominant-inherited skeletal malformations caused by bone hypoplasia, including Larsen syndrome (LS), atelosteogenesi-I (AO-I), atelosteogenesi-I (AO-III) and boomerang dysplasia (BD). Among this spectrum of diseases, LS causes a milder hypoplasia of the skeletal system, compared to BD's much more severe symptoms. Previous studies revealed limited molecular mechanisms of FLNB-related diseases but most of them were carried out with HEK293 cells from the kidney which could not reproduce FLNB's specificity to skeletal tissues. Instead, we elected to use ATDC5, a chondrogenic stem cell line widely used to study endochondral osteogenesis. In this study, we established FLNB-transfected ATDC5 cell model. We reported a pedigree of LS with mutation of FLNBG1586R and reviewed a case of BD with mutation of FLNBL171R . Using the ATDC5 cell model above, we compared cellular and molecular phenotypes of BD-associated FLNBL171R and LS-associated FLNBG1586R . We found that while both phenotypes had an increased expression of Runx2, FLNBL171R-expressing ATDC5 cells presented globular aggregation of FLNB protein and increased cellular apoptosis rate while FLNBG1586R-expressing ATDC5 cells presented evenly distributed FLNB protein and decreased cellular migration. These findings support our explanation for the cause of differences in clinical phenotypes between LS and BD. Our study makes a comparative analysis of two extremes of the FLNB-mutated autosomal dominant spectrum, relating known clinical phenotypes to our new cellular and molecular findings. These results indicated next steps for future research on the role of FLNB in the physiological process of endochondral osteogenesis.

Identification of mutations in the prostaglandin transporter gene SLCO2A1 and phenotypic comparison between two subtypes of primary hypertrophic osteoarthropathy (PHO): A single-center study.

Primary hypertrophic osteoarthropathy (PHO) is an inherited disease characterized by digital clubbing, periostosis, and pachydermia. Based on two causative genes, hydroxyprostaglandin dehydrogenase (HPGD) and solute carrier organic anion transporter family member 2A1 (SLCO2A1), PHO is categorized into two subtypes: hypertrophic osteoarthropathy, primary, autosomal recessive 1 (PHOAR1) and hypertrophic osteoarthropathy, primary, autosomal recessive 2 (PHOAR2). In this study, we summarized the clinical manifestations and analyzed SLCO2A1 gene in 23 PHOAR2 patients in our center. As a result, 18 patients displayed complete phenotypes of PHO with digital clubbing, periostosis, and pachydermia. 29 mutations were found in total, and 22 of them were novel mutations including 13 missense, three nonsense, four deletion, one frame-shift and one splicing site mutations. Compared with nine PHOAR1 patients we previously reported, PHO patients with SLCO2A1 mutations were all male and presented with a later onset age. Peptic ulcers and myelofibrosis occurred only in PHOAR2 patients. The urinary level of prostaglandin E2 metabolite (PGEM) is significantly higher in PHOAR2 patients than that in PHOAR1 group. In conclusion, this study was the largest cohort to date to summarize PHOAR2 patients and to assess the phenotypic difference between two subtypes of PHO. The difference of urinary PGEM concentration between two subtypes is helpful for the differential diagnosis of PHO.

Vascular Ehlers-Danlos Syndrome With a Novel Missense COL3A1 Mutation Present With Pulmonary Complications and Iliac Arterial Dissection.

Vascular Ehlers-Danlos syndrome (vEDS) is a life-threatening connective tissue disorder due to its high tendency of arterial and organ rupture. Pulmonary complications in vEDS are rare. We present a young male patient with vEDS who developed severe pulmonary complications and severe rupture of the iliac artery at different stages of his life. Vascular Ehlers-Danlos syndrome was diagnosed based on clinical manifestations and confirmed by the identification of COL3A1 gene mutation. Due to high bleeding tendency and weak cardiopulmonary capacity, conservative treatment was taken for him. To our knowledge, this is the first report of vEDS case in which the patient developed both pulmonary complications and dissection of large arteries. Our report emphasizes the importance of considering vEDS when an adolescent develops unexplained pulmonary cysts with fragility of lung tissues. Genetic counseling and close monitoring should be performed for earlier diagnosis and prevention of severe complications of large arteries. The typical presentations of vEDS were also discussed by means of a review of case reports on vEDS with pulmonary complications.