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Background Pseudohypoparathyroidism is a rare genetic disease characterized by hypocalcaemia and hyperphosphataemia due to the defect to the guanine nucleotide-binding protein alpha subunit (GNAS) gene. Patients with pseudoparathyroidism type 1a and 1c could manifest Albright’s hereditary osteodystrophy and multiple hormone resistance including gonadotropin and thyroid stimulating hormone. Case presentation Here we report a Chinese man who presented with fatigue, recurrent seizure and Albright’s hereditary osteodystrophy. His genetic study revealed a heterozygote mutation in the GNAS gene [NM_000516.4(GNAS): c2787_2788del (p.Val930AspfsTer12)]. After calcium and calcitriol supplement, his seizures achieved partially remission. Conclusions We report a case of PHP1a or 1c with a novel frameshift mutation in GNAS gene in a patient presenting with AHO, as well as TSH and partial gonadotropin resistance. This mutation in this case has not been reported in literature and adds to the spectrum of genetic mutations related to PHP.

Chronic kidney disease affects patients of all ages and, as it progresses, it greatly affects their lives, especially with the complications it causes. One major complication is renal osteodystrophy (ROD) which starts to develop from the early stages of the disease, but becomes most apparent in patients in need of renal replacement therapy. Diagnosing ROD in the early stages remains a challenge, which brings up the need to find novel biomarkers. Studies are focusing on the role of fibroblast growth factor 23 and Klotho in the bone and mineral homeostasis, but the results are conflicting. ROD remains a major complication in CKD patients, therefore we need to gain a better understanding from the pathophysiological point of view, in order to be able to adjust the medical therapy.

Objectives Objectives Pseudohypoparathyroidism type 1A (PHP1A) is caused by maternal inheritance of GNAS mutations. It is characterized by the resistance to several hormones, primarily the parathyroid hormone (PTH), and the features of Albright’s hereditary osteodystrophy. Case presentation Here, we present a family comprised two affected brothers with PHP1A and identify a novel mutation (c.277C>T) in the GNAS gene. The siblings developed a slightly different presentation in the same clinical condition. Although both patients presented with PTH resistance, which is the hallmark of PHP, the proband showed the thyroid-stimulating hormone resistance with the progression of heterotopic ossification from skin and subcutaneous tissue into deep connective tissue, while the younger brother with normocalcemia did not show the resistance to other hormones. The patients may inherit the mutation from their mother who presumably carries the mutation as a mosaicism. Conclusions Our case highlights the significance of considering mosaicism as an explanation for apparent de novo cases of pseudohypoparathyroidism.

It is known that deformity of the hooves is one of the most common lesions, the main cause of which is a violation of the relationship between the speed of regrowth and abrasion of the hoof horn. It develops gradually and initially does not cause changes in the organism of cows, but later leads to various diseases, including orthopedic. It is determined that in alimentary osteodystrophy (results of multifactorial mass-volume analysis and prolonged osteotendinitis of the finger flexors) and irregular corrective cleaning of the hooves and formed triggered deformation of the hooves, which leads to a violation of the support-force interactions contributes to the emergence and development of aseptic subdermatitis of chronic genesis, which is clinically appeared by lameness animals addiction, careful stepping from limb to limb, fatigue, shortening of step, etc. Simultaneously, there are changes from a bone tissue. Thus, in the area of the sole of the hoof bone, single or multiple osteophytes and exostoses are formed, which are formed in the process of ossification and metabolic disorders. According to chronic aseptic pododermatitis in cows there is a deterioration in the quality of the hoof horn, as indicated by the results of biochemical and biophysical searches. In particular, there is a decrease in calcium, sulfur, an increase in the concentration of SH-groups, a decrease in the concentration of copper, zinc, cobalt, which leads to a decrease in the density and hardness of the hoof horn, as well as an increase in abrasion resistance and a decrease in the intensity of abrasion of the horn of the animal sole, which leads to an accruing in the horn of the sole and dysfunction of the musculoskeletal system.

International audience; Active vitamin D analogs and calcimimetics are the main therapies used for treating secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD). Peripheral blood mononuclear cells of 19 pediatric patients with CKD1-5D and 6 healthy donors (HD) were differentiated into mature osteoclasts with receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). The effects of single or combined treatment with active vitamin D (1.25-D) and/or calcimimetic KP2326 were evaluated on osteoclastic differentiation and osteoclastic-mediated bone resorption. Although 1.25-D inhibited osteoclastic differentiation, a significant resistance to 1.25-D was observed when glomerular filtration rate decreased. A significant albeit less important inhibitory effect of KP2326 on osteoclastic differentiation was also found both in cells derived from HD and CKD patients, through a putative activation of the Erk pathway. This inhibitory effect was not modified by CKD stage. Combinatorial treatment with 1.25-D and KP2326 did not result in synergistic effects. Last, KP2326 significantly inhibited osteoclast-mediated bone resorption. Both 1.25-D and KP2326 inhibit osteoclastic differentiation, however, to a different extent. There is a progressive resistance to 1.25-D in advanced CKD that is not found with KP2326. KP2326 also inhibits bone resorption. Given that 1.25-D has no effect on osteoclastic resorption activity and that calcimimetics also have direct anabolic effects on osteoblasts, there is an experimental rationale that could favor the use of decreased doses of 1.25-D with low doses of calcimimetics in SHPT in dialysis to improve the underlying osteodystrophy. However, this last point deserves confirmatory clinical studies. © 2020 American Society for Bone and Mineral Research.

BACKGROUND: From 1980s to the new millennium, the number of patients surviving with end stage renal disease (ESRD) has increased by 3 fold. This is driven by early detection of primordial and primary risk factors, state of the art renal replacement therapy and ease of public access to healthcare. Renal osteodystrophy (RO) is a metabolic bone disease causing significant morbidity in patients with ESRD, in particular fragility fractures. In this case series, we present the surgical management of 3 ESRD patients with pathological fractures of the neck of femur (NOF) and surgical treatment (parathyroidectomy) of tertiary hyperparathyroidism of ESRD patients in the same surgical setting. Up to date there has been no reports on bipolar hemiarthroplasty and total parathyroidectomy implemented in the same operative setting. METHODS: We present 3 cases, 2 males and a female with an average age of 48 years. All patients presented with no trauma or minimal trauma. With high index of suspicion and after confirming the diagnosis with advanced imaging, the patients underwent cemented modular hemiarthroplasty with posterior approach. Parathyroidectomy was sequentially performed to address the tertiary hyperparathyroidism at the same setting. We followed them for 48 months. RESULTS: At 48-month follow up, all the patients were at their pre-morbid ambulatory status and there were no major complications. They did not need any revision surgery or re-operation either for the hemiarthroplasty surgery or the parathyroidectomy during the follow up period. CONCLUSION: To avoid diagnostic pitfalls in this group of patients we recommend MRIs of both hips in patients complaining of unilateral hip pain even when the roentgenograms are clear of fractures. Total parathyroidectomy at the same setting with the bipolar hemi-arthroplasty is a safe combination. This reduces the anaesthesia risk, the recovery time as well as the equilibrium time for calcium homeostasis.

Anonychia refers to the absence of nail plates owing to an autosomal dominant or recessive inheritance. Congenital anonychia is a rare condition that may be associated with other ectodermal or mesodermal malformations like epidermolysis bullosa, (deafness, onychodystrophy, osteodystrophy, and mental retardation) syndrome and Iso-Kikuchi syndrome. Here, we report 3 cases with anonychia congenita appearing in different generations of a single family in Kingdom of Saudi Arabia.

Pseudohypoparathyroidism (PHP), characterized by multihormone resistance and Albright’s hereditary osteodystrophy (AHO), is caused by GNAS mutations. Whole or partial gene deletions are rare. All disorders due to inactivating mutations of the GNAS gene are now classified as “inactivating PTH/PTHrP signaling disorder type 2” (iPPSD2). This study reports a family harboring a large GNAS gene deletion in order to improve the knowledge of genotype–phenotype correlation of this disease. An 18-year-old man with severe diffuse soft ossifications and multihormone resistance underwent to clinical, biochemical, radiological, and genetic studies. A review of the literature of other cases of iPPSD2 due to GNAS large deletions was performed focusing on clinical and biochemical features. The proband presented signs of hypocalcemia and marked AHO features. Laboratory tests revealed hypocalcemia, high levels of serum phosphate, PTH, TSH, and calcitonin despite therapy with calcium carbonate, calcitriol, and levothyroxine. Diffuse soft tissue ossifications and brain calcifications were shown by radiological exams. Family history was remarkable for hypocalcemia, neurocognitive impairment, and cerebral calcifications in his brother and AHO features in the maternal grandfather. The proband’s mother showed short stature, whereas physical examination of the father was unremarkable. Genetic analysis of the GNAS gene revealed an unreported large deletion encompassing exons 1–7 in the proband, brother, and mother. By reviewing the literature, only six other cases were described. We report a kindred harboring a large GNAS deletion. A genotype–phenotype correlation was observed in term of severity of tissue ossifications in the siblings but not in the mother.

The use of bone biopsy for histomorphometric analysis is a quantitative histological examination aimed at obtaining quantitative information on bone remodeling, structure and microarchitecture. The labeling with tetracycline before the procedure also allows for a dynamic analysis of the osteoblastic activity and mineralization process. In the nephrological setting, bone biopsy is indicated to confirm the diagnosis of subclinical or focal osteomalacia and to characterize the different forms of renal osteodystrophy (ROD). Even if bone biopsy is the gold standard for the diagnosis and specific classification of ROD, the use of this approach is very limited. The main reasons for this are the lack of widespread expertise in performing or interpreting bone biopsy results and the cost, invasiveness and potential pain associated with the procedure. In this regard, the sedation, in addition to local anesthesia routinely applied in Italian protocol, significantly reduces pain and ameliorates the pain perception of patients. Concerning the lack of widespread expertise, in Italy a Hub/Spokes model is proposed to standardize the analyses, optimizing the approach to CKD patients and reducing the costs of the procedure. In addition, new tools offer the possibility to evaluate the osteogenic potential or the ability to form bone under normal and pathological conditions, analyzing mesenchymal stem cells and their ability to differentiate in the osteogenic lineage. In the same way, circulating microRNAs are suggested as a tool for exploring osteogenic potential. The combination of different diagnostic approaches and the optimization of the bioptic procedure represent a concrete solution to spread the use of bone biopsy and optimize CKD patient management.

Reports on the prevalence of torus mandibularis among dialysis patients have been limited and inconclusive. A wide variety of oral manifestations has been found in patients with hyperparathyroidism. Furthermore, uremia-related changes in facial bone structures have been described in the literature. This prospective observational study examined 322 hemodialysis patients treated at the Chang Gung Memorial Hospital from 1 August to 31 December 2016. Two subgroups were identified: patients with torus mandibularis (n = 25) and those without (n = 297). Clinical oral examinations including inspection and palpation were employed. Our study found that most mandibular tori were symmetric (84.0%), nodular (96.0%), less than 2 cm in size (96.0%), and located in the premolar area (92.0%). Poor oral hygiene was observed among these patients, with 49.7% and 24.5% scoring 3 and 4, respectively, on the Quigley-Hein plaque index. More than half (55.0%) of patients lost their first molars. Multivariate logistic regression analysis revealed that blood phosphate level (odds ratio = 1.494, p = 0.029) and younger age (odds ratio = 0.954, p = 0.009) correlated significantly with torus mandibularis. The prevalence of torus mandibularis in patients receiving hemodialysis in this study was 7.8%. Younger age and a higher blood phosphate level were predictors for torus mandibularis in these patients.

In 1980, Farfel and colleagues (NEJM, 1980;303:237–42) provided first evidence for two distinct variants of pseudohypoparathyroidism (PHP) that present with hypocalcemia and impaired parathyroid hormone (PTH)‐stimulated urinary cAMP and phosphate excretion, either in the presence or absence of Albright's hereditary osteodystrophy (AHO). An “abnormal allele” and an “unexpressed allele” were considered as underlying defects, predictions that turned out to be correct for both forms of PHP. Patients affected by the first variant (now referred to as PHP1A) were later shown to be carriers of inactivating mutations involving the maternal GNAS exons encoding Gsα. Patients affected by the second variant (now referred to as PHP1B) were shown in the current study to carry a maternal 3‐kb STX16 deletion, the most frequent cause of autosomal dominant PHP1B, which is associated with loss of methylation at GNAS exon A/B that reduces or abolishes maternal Gsα expression. However, the distinct maternal mutations leading to either PHP1A or PHP1B are disease‐causing only because paternal Gsα expression in the proximal renal tubules is silenced, ie, “unexpressed.” Our findings resolve at the molecular level carefully conducted investigations reported some 41 years ago that had provided first clues for the existence of two distinct PHP variants. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Background The GNAS gene on chromosome 20q13.3 is a complex, imprinted locus regulated in a tissue-specific manner. GNAS inactivation disorders are a heterogeneous group of rare disorders caused by mutations and methylation defects. These are divided into pseudohypoparathyroidism (PHP) types 1A and 1B, pseudo-pseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH), depending on the presence or absence of hormone resistance, Albright’s hereditary osteodystrophy (AHO), and ectopic ossification. Methods This study analyzed the clinical characteristics and molecular genetic backgrounds of 18 Korean patients from 16 families with a genetically confirmed GNAS defect. Auxological parameters, AHO phenotypes, types of hormonal resistance, family history, and molecular genetic disturbances were reviewed retrospectively. Results Nine (90%) patients with PHP1A showed resistance to parathyroid hormone (PTH) and all patients showed elevated thyroid-stimulating hormone (TSH) levels at diagnosis. Eight (80%) patients were managed with levothyroxine supplementation. Three of six patients with PHP1B had elevated TSH levels, but none of whom needed levothyroxine medication. AHO features were absent in PHP1B. Patients with PPHP and POH did not show any hormone resistance, and both of them were born as small for gestational age. Among the 11 families with PHP1A, PPHP, and POH, eight different (three novel) mutations in the GNAS gene were identified. Among the six patients with PHP1B, two were sporadic cases and four showed isolated loss of methylation at GNAS A/B:TSS-DMR. Conclusions Clinical and molecular characteristics of Korean patients with GNAS inactivation disorders were described in this study. Also, we reaffirmed heterogeneity of PHP, contributing to further accumulation and expansion of current knowledge of this complex disease.

Mutations that disrupt the TBC1D24 presynaptic protein have been implicated in various neurological disorders including epilepsy, chronic encephalopathy, DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures) syndrome, nonsyndromic hearing loss, and myoclonus. We present the case of a 22-month-old male with infantile-onset paroxysmal episodes of facial and limb myoclonus. The episodes were linked to biallelic variants in exon 2 of the TBC1D24 gene that lead to amino acid changes (c.304C >T/p.Pro102Ser and c.410T > C/p.Val137Ala), each variant being inherited from a parent. Follow-up imaging in adolescence revealed widened right cerebellar sulci. We discuss the evolving landscape of TBC1D24 associated phenotypes; this case adds to a growing body of evidence linking this gene to movement disorders in children.

Osteogenesis imperfecta (OI) is a rare congenital osteodystrophy. Patients with OI present with osteoporosis, extreme bone fragility and severe deformities of the lower limbs, which predispose them to frequent fractures. The aim of our study is to describe the minimally invasive osteotomy technique to correct the tibial deformities in patients with OI type III, using the Fassier-Duval (FD) intramedullary nailing, which is considered the gold standard in this kind of surgery. We analyzed the results obtained from 14 patients with OI type III, treated for tibial deformities with the minimally invasive percutaneous osteotomy technique and osteosynthesis with the FD telescopic nail. The results were compared with that of a control group composed of 18 patients with OI type III, treated for tibial deformities with open technique osteotomies and osteosynthesis with FD telescopic nail. The follow-up was set at 18 months postoperatively. The data concerning the following were collected from the two groups: duration of surgery, number of osteotomies performed, postoperative pain, time required for functional recovery, and for the formation of bone callus. To analyze the variations in the quality of life, all the patients were given the Pediatric Outcomes Data Collection Instrument questionnaire, before surgery and at the end of the follow-up. In patients who underwent corrective surgery with the percutaneous technique, the average duration of surgery was inferior, the postoperative pain was significantly lower, the recovery of 90° range of motion of knee flexion was reached at an average of 37.8 days, and they ambulated bearing full weight on the leg without auxiliary aids on average 45 days after surgery. The Pediatric Outcomes Data Collection Instrument questionnaire values were satisfactory in both groups. The osteosynthesis with the FD telescopic nail, performed with the minimally invasive surgical technique, has improved the management of deformities in OI. The minimally invasive technique, however, requires the maturation of three distinct learning curves: surgery on patients with OI, open technique with the FD nail, and percutaneous technique with the FD nail.

Pseudohypoparathyroidism type 1A (PHP1A) is usually diagnosed in childhood or early adulthood. We describe the case of a 64-year-old woman admitted to the Neurological Unit for recurrent episodes of loss of consciousness and seizures. Glycemia and ECG were normal, while hypocalcemia was noted. Clinical history revealed carpo-pedal spasm since the age of 30 years, cognitive impairment, hypothyroidism since early adulthood, and menopause at 30 years. She was taking oral calcium and cholecalciferol for chronic hypocalcemia. Physical features suggested Albright’s osteodystrophy. Blood calcium was confirmed low, with increased parathyroid hormone, moderate 25OH-vitamin D deficiency, and normal creatinine. Brain CT scan revealed calcifications of the basal ganglia, cortical and subcortical white matter, and cerebellum. Therapy was switched to oral calcitriol, with normalization of calcium levels; levetiracetam was started and no further seizures occurred. The clinical diagnosis of PHP1A was confirmed by molecular analysis, which demonstrated the heterozygous c.568_571del mutation of the GNAS gene. Our report illustrates the natural history of a patient with PHP1A, which went undiagnosed until the age of 64 years, with multi-hormonal resistance and clinical sequelae evolving throughout life, and underlines the importance of diagnosing this rare disease, which has a great impact on patients and their family life.

Background: Disordered metabolism of bone and minerals is a problem frequently encountered in patients with chronic kidney disease. Early biochemical changes include altered calcium and phosphate balance, while advanced disease produces reduced bone strength and extraskeletal calcification. The syndrome describing this constellation of findings is termed chronic kidney disease mineral and bone disorder. Case Report: This report details a rare and extreme manifestation of chronic kidney disease mineral and bone disorder in a patient on long-term hemodialysis for end-stage renal failure. Progressive abnormalities of the thoracic skeleton were ultimately severe enough to produce restrictive lung physiology and symptomatic respiratory failure. Conclusion: Cases of chronic kidney disease mineral and bone disorder with pronounced clinical sequelae occur uncommonly in contemporary practice because of early detection and effective therapies. To our knowledge, this report is the first case in the literature of severe thoracic involvement manifesting as respiratory failure.

Introduction Hepatic osteodystrophy is an osteoporotic bone disease that occurs in chronic liver disease patients. The global prevalence of osteoporosis in patients with chronic liver disease is 30% to 40%. The pathogenesis of hepatic bone disease is not clear, but it occurs due to unstable bone remodeling with increased bone resorption and decreases bone formation. There has been an interest in determining the clinical utility of bone turnover markers (BTMs) in the assessment of osteoporosis in chronic liver patients. Methods This was a cross-sectional study conducted in patients with chronic liver disease at the section of chemical pathology, department of pathology and laboratory medicine, Aga Khan University (AKU). A total of 50 patients with age >8 years and a history of liver disease >6 months were recruited from January to October 2019. Liver function tests, i.e. aspartate aminotransferase (AST), alanine transaminase (ALT), albumin, and bilirubin, along with clinical signs of liver disease chronicity, were noted. The samples for BTMs, i.e. total serum alkaline phosphatase (ALP) and serum C-terminal telopeptide of type-1 collagen (CTX) were withdrawn and analyzed on Microlab (ELItech Group, Puteaux, France) and ADVIA Centaur (Siemens Diagnostics, NY), respectively. Results The majority of patients were males (n=34, 68%). Twenty-four (48%) patients suffered from fibrosis while 26 (52%) were without fibrosis. Median platelet count (68×109/L (102.5-50)) and median cholesterol levels (102.5 mg/dl (147-99.5)) were decreased, whereas gamma-glutamyl transferase (GGT) levels were higher in the fibrosis group as compared to the non-fibrosis group. The median levels of total ALP were 91.5 IU/L (103-82), and the median levels of CTX were 0.24 pg/ml (0.34-0.21). Conclusion In the present study, no significant difference was found in the BTMs of patients with and without chronic liver disease (CLD). However, there was a positive and significant correlation of BTMs, particularly CTX with age, bilirubin levels, and hepatomegaly.

Publisher Copyright: © 2021, The Author(s). Bone histomorphometric analysis is the most accurate method for the evaluation of bone turnover, but non-invasive tools are also required. We studied whether bone biomarkers can predict high bone turnover determined by bone histomorphometry after kidney transplantation. We retrospectively evaluated the results of bone biopsy specimens obtained from kidney transplant recipients due to the clinical suspicion of high bone turnover between 2000 and 2015. Bone biomarkers were acquired concurrently. Of 813 kidney transplant recipients, 154 (19%) biopsies were taken at a median of 28 (interquartile range, 18–70) months after engraftment. Of 114 patients included in the statistical analysis, 80 (70%) presented with high bone turnover. Normal or low bone turnover was detected in 34 patients (30%). For discriminating high bone turnover from non-high, alkaline phosphatase, parathyroid hormone, and ionized calcium had the areas under the receiver operating characteristic curve (AUCs) of 0.704, 0.661, and 0.619, respectively. The combination of these markers performed better with an AUC of 0.775. The positive predictive value for high turnover at a predicted probability cutoff of 90% was 95% while the negative predictive value was 35%. This study concurs with previous observations that hyperparathyroidism with or without hypercalcemia does not necessarily imply high bone turnover in kidney transplant recipients. The prediction of high bone turnover can be improved by considering alkaline phosphatase levels, as presented in the logistic regression model. If bone biopsy is not readily available, this model may serve as clinically available tool in recognizing high turnover after engraftment.

Purpose: Progressive osseous heteroplasia (POH), a genetic disorder, is associated with Albright’s hereditary osteodystrophy (AHO), pseudohypoparathyroidism, and primary osteoma cutis and has common features of superficial ossification and GNAS-inactivating mutations. Disorders due to GNAS­-inactivating mutations are classified as “inactivating parathyroid hormone (PTH)/PTHrP signaling disorder type 2.” This study reports a case of mild POH overlap syndrome to improve understanding of genotype–phenotype correlations.Methods: A 13-year-and-6-month-old Japanese boy was referred to our hospital with a chief complaint of the lower limb length difference. He underwent clinical, biochemical, radiological, and genetic studies.Results: He showed sporadic GNAS mutation, deep ectopic ossification, small for gestational age (SGA), congenital tooth defect, and lack of AHO features; he met the diagnostic criteria for POH, and mild PTH and TSH resistance was detected. He had constant hyperphosphatasemia and hypocalciuria. At the age of 10 years, he occasionally experienced high iPTH levels. The pituitary stimulation test showed a normal response of all hormones at 3 years of age, but TSH response was decreased (previously 0.770, peak value 4.144 μIU/mL) in the TRH loading test at age 13 years and 6 months. DNA analysis showed a heterozygous p.D189MfsTer14 mutation of GNAS. The parents did not carry this mutation.Conclusion: We report a rare case of POH overlap syndrome with PTH/TSH resistance that appeared in adolescence rather than early childhood. Cases diagnosed with POH in early childhood also require reassessment during adolescence. Further studies of the GNAS heterozygous mutation p.D189MfsTer14 may reveal factors involved in POH overlap syndrome.

Objectives: To study computed tomography findings in Paget's disease of temporal bone (PDTB) and analyze the relations between otic capsule bone mineral density values measured in Hounsfield Units (HU) and hearing loss (HL). Study Design: Observational case-control study. Setting: Tertiary referral center. Patients: Radiographically confirmed PDTB cases and control group. Intervention: Diagnostic. Main Outcome Measures: Hearing thresholds and computed tomography bone density values. Results: Twenty-three ears in the case group (PDTB) and 27 control ears were included. In the PDTB group, HL was found in 87% of the ears (43% mixed) and an air-conduction threshold of 50.7 dB (SD = 19.8). In the control group, 48% of the ears showed HL (7% mixed) and an air-conduction threshold of 34.5 dB (SD = 20.6) was found; the difference was statistically significant (p < 0.05). Measurements of bone density (HU) in the otic capsule (regions of interest [ROI] 1 and 2) and in the petrous bone (ROI 3) were significantly lower (p < 0.05) in the PDTB group than in controls. The PDTB group presented a significant association between otic capsule bone density in ROI 1 and mean otic capsule density with air and bone-conduction thresholds (p < 0.05). In controls, no association was observed between any density value and audiometric thresholds. Conclusion: PDTB patients showed more frequent HL, lower thresholds, and a higher proportion of mixed HL than controls. Bone density (HU) was decreased in all ROIs in PDTB patients in comparison with controls. Bone density in the otic capsule was associated with HL in PDTB patients, but no association was observed between bone density and HL in controls.

Objective We present a patient with pseudopseudohypoparathyroidism (PPHP) who developed both gout and synovial chondromatosis, in addition to the classical Albright's hereditary osteodystrophy phenotype. Methods The patient's clinical course, laboratory data, and imaging are presented. Results The patient is a 40-year-old male with no pertinent family history who presented with findings of Albright's hereditary osteodystrophy, including short stature, obesity, rounded face, shortened fourth and fifth digits, and osteoma cutis (heterotopic subcutaneous ossification), which required surgical removal for pain relief. Genetic testing confirmed a GNAS mutation, and labs showed normal parathyroid hormone, calcium, and phosphorus levels, diagnostic of PPHP. The patient later developed gout and synovial chondromatosis, a rare benign process where the synovial membrane forms calcified loose bodies within the joint. Conclusion The patient case highlights the musculoskeletal complications of PPHP. Though PPHP has been rarely associated separately with gout or synovial chondromatosis, this is the first reported patient to have developed both conditions. This case raises the significance of multidisciplinary follow up for potential orthopedic complications. Moreover, the case underscores the importance of genetics and epigenetics in skeletal health, independent of calcium homeostasis in the blood.

It is considered important to use the prognostic tasks of the mathematical method using modern information and communication technology. Noticeable changes have been made in the development of the computer diagnostic system, for studying types of diseases in the field of veterinary medicine, the occurrence of the causes of diseases, and improving the quality of targeted treatment methods.A prognostic model using a fuzzy set has been created to study clinical factors and the likelihood of secondary osteodystrophy in cows.

Growth retardation, decreased final height, renal osteodystrophy (ROD), and vascular calcifications are common complications of CKD in pediatric dialysis patients, resulting from a combination of abnormalities in the growth hormone (GH) axis, vitamin D deficiency, hyperparathyroidism, hypogonadism, inadequate nutrition, cachexia, and drug toxicity. The impact of CKD-associated bone and mineral disorders (CKD-MBD) may be immediate (abnormalities of bone and mineral metabolism) or delayed (poor growth, bone deformities, fractures, vascular calcifications, increased morbidity and mortality).

Background DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation and seizures; MIM 220500) is a rare multisystem genetic disorder, mainly characterized by sensorineural deafness, shortened terminal phalanges with small nails of hands and feet, intellectual deficit, and seizures. The disease is caused by homozygous or compound heterozygous mutation in the TBC1 domain family member 24 (TBC1D24) gene (gene locus/MIM 613577) on chromosome 16p13. Objectives We report the first case of DOORS syndrome from Indonesia. Materials and methods A review of the literature was conducted and cases compared. Results A 27-day-old baby girl was brought to us with a history of recurrent seizures and absence of all finger- and toenails since birth. In addition, physical examination revealed left eye strabismus and a single transverse palmar crease on both hands. X-rays of the hands and feet showed absence of the distal phalanx of her right and left fingers II-V and the distal phalanx of her right and left toes I-V, respectively. Brainstem-evoked response audiometry test revealed profound bilateral sensorineural deafness. Pentalogy of Fallot was diagnosed by echocardiography, while an abnormal diffuse epileptiform pattern was found on electroencephalography. Conclusion This is the first report of an association between pentalogy of Fallot and single transverse palmar crease in DOORS syndrome.

DOORS [deafness, onychodystrophy, osteodystrophy, intellectual disability (mental retardation), and seizures] syndrome can be caused by mutations in the TBC1D24 and ATP6V1B2 genes, both of which are involved in endolysosomal function. Because of its extreme rarity, to date, no detailed neuropathological assessment has been performed to establish clinicopathological relationships and, thereby, understand better the neurobiology of this disease in aged cases. Accordingly, the aim of the current study was to highlight the clinicopathological characteristics of a novel case with a presumable de novo mutation in the ATP6V1B2 gene from a neuropathological point of view. This Caucasian male patient, who died at the age of 72 years, presented all the typical cardinal signs of DOORS syndrome. In addition, behavioral alterations, pyramidal signs, and Parkinsonism were observed. The p.R506X pathogenic mutation identified in the ATP6V1B2 gene was responsible for the clinical phenotype. The detailed neuropathological assessment revealed a limbic-predominant tauopathy in the forms of argyrophilic grain disease, primary age-related tauopathy, and age-related tau-astrogliopathy. In summary, we present the first detailed clinicopathological report of a patient with DOORS syndrome harboring a pathogenic mutation in the ATP6V1B2 gene. The demonstrated tauopathy may be considered as a consequence of lysosomal and/or mitochondrial dysfunction, similar to that found in Niemann-Pick type C disease, which is another lysosomal disorder characterized by premature neurodegenerative disorder.

DOORS syndrome is characterized by deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. In this study, we report two unrelated individuals with DOORS syndrome without deafness. Exome sequencing revealed a homozygous missense variant in PIGF (NM_173074.3:c.515C>G, p.Pro172Arg) in both. We demonstrate impaired glycosylphosphatidylinositol (GPI) biosynthesis through flow cytometry analysis. We thus describe the causal role of a novel disease gene, PIGF, in DOORS syndrome and highlight the overlap between this condition and GPI deficiency disorders. For each gene implicated in DOORS syndrome and/or inherited GPI deficiencies, there is considerable clinical variability so a high index of suspicion is warranted even though not all features are noted.

Objectives The objective of this paper is to report a peculiar case of a patient with pseudohypoparathyroidism type 1b (PHP1B). Pseudohypoparathyroidism (PHP) refers to a group of disorders characterized by hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) concentrations as the result of end-organ unresponsiveness to PTH. Case presentation We present a 14-year-old boy, who was admitted with severe symptomatic hypocalcaemia, absence of dysmorphic features and Albright's hereditary osteodystrophy features. Laboratory investigations revealed markedly low serum calcium, high phosphate, markedly elevated PTH levels and vitamin D insufficiency, while magnesium, albumin, ALP and TSH were normal. The clinical and laboratory findings were consistent with PHP1B. Molecular analysis revealed loss of methylation at the AB DMR of the GNAS locus, confirming the diagnosis. Yet no STX16 deletion was detected. Conclusions It is possible that delSTX16- patients carry a defect in an element that controls the methylation both at the GNAS-A/B DMR and at the GNAS-AS2. This rare case emphasizes the need of individualized molecular analysis in PHP1B patients in order to elucidate the possible molecular defect.

Current multifactorial age estimation methods are based on radiography, however, in the forensic field there is growing interest in using magnetic resonance imaging (MRI). With regard to the carpal region, MRI provides more information for defining the individual ossification nuclei and the cartilage surrounding single bones. During the phase of bone growth, the progressive reduction of the cartilage layer is accompanied by the development of a cartilage-bone interface. The aim of our study was to create a new model for age estimation, based on the ratio between the area occupied by the nucleus of ossification (NO) and the surface of growth (SG) of each carpal bone, the latter derived by adding NO to the area of cartilage-bone interface. We analyzed 57 MRI scans of Italian subjects aged between 12 and 20 years, without growth diseases, endocrine disorders or osteodystrophy. Measurements of NO and SG areas were extracted using ImageJ software, and the ratio between the NO and SG of each bone (NOSG) was calculated. A multiple linear regression model was used to estimate the individual's age as a function of the variables: gender and wrist bone measurements. The results showed that the best model was obtained with 6 predictors (nvmax=6): Gender, and the NOSG of the Trapezoid, Trapezium, Scaphoid, Pisiform, and Capitate. The median of the residuals (observed age minus predicted age) was -0.025 years, with an IQR of 0.19 years. Thus a new forensic approach to age assessment using MRI is introduced in this paper, which gives the preliminary results.

Metabolic spine disease lies on the dynamic nature of bone constantly changing and adapting in response to load variations in the body. The ability of magnetic resonance imaging (MRI) to detect even the slightest changes in water content makes it an invaluable tool for imaging soft tissue pathology and edema associated with metabolic diseases of the spine. Furthermore, MRI can also serve as a preoperative guide for the treatment of such diseases. In this chapter, we summarize and discuss osteoporosis, Paget’s disease, and renal osteodystrophy. The pathophysiology of each disease is reviewed briefly, along with the American College of Radiology (ACR) Appropriateness Criteria, relevant findings on MRI, and how these findings can be used by the orthopedic surgeon to diagnose and treat patients suffering from these diseases.

Introduction. Fahr's syndrome is an infrequent disorder characterized by bilateral symmetrical calcification of basal ganglia and the cerebral cortex. It can be seen genetic, idiopathic, or secondary to endocrine diseases. This disease is related to different metabolic disorders particularly with diseases of the parathyroid gland. Case 1. A 63-year-old female patient applied to our clinic due to having hypoparathyroidism with bilateral basal ganglia calcification in head computed tomography(CT). She had subtotal thyroidectomy 25 years ago. in the neurological examination, mild symmetrical parkinsonism was determined. in laboratory examination Ca:8 mg/dL (8.6- 10.2), P:5.1 mg/dL (2.3-4.5), PTH:9.53 pg/mL (15-65) were detected. Calcitriol 0.25 mu/day was added to her treatment. Her parkinsonism disappeared after the treatment. Case 2. A 49-year-old male patient was consulted when he was admitted to the department of neurology in our hospital. the physical examination demonstrated the characteristics of Albright's hereditary osteodystrophy. the neurological examination shows bilateral symmetrical bradykinesia, dysphagia, and moderate dysarthria. in the laboratory examination PTH: 46.5 ng/L(15-65), Ca:8.6 mg/dL (8.6-10.2), P:2.7 mg/dL (2.3-4.5) were detected and were all within the normal ranges. Consequently, pseudopseudohypoparathyroidism was decided as a diagnosis. G protein alpha subunit mutation (Gs alpha) was not detected due to technical limitations. Conclusion. When a patient is diagnosed as Fahr's syndrome, we should keep in mind parathyroid disorders. Fahr's syndrome must be evaluated in patients showing intracranial calcification accompanied by parathyroid diseases.

Primary hyperparathyroidism (PHPT) is caused by parathyroid malignant neoplasm in 1% of cases. The risk of the latter is higher in patients with symptomatic PHPT. The prognosis in this group of patients depends on the extent of the process and primary surgical intervention. In these cases, the differential diagnosis between secondary foci in the bones associated with parathyroid cancer and hyperparathyroid osteodystrophy is a challenging problem. This article describes two cases of severe PHPT accompanied by hyperparathyroid osteodystrophy suspected for metastatic parathyroid cancer. Positron emission tomography in combination with computed tomography (PET/CT) with 18F-fluorodeoxyglucose (18F-FDG) and/or 18F-fluorocholine was included in the examination algorithm. In both cases, pronounced bone changes similar to parathyroid metastases were observed. Accumulation of 18F-fluorocholine was also observed only in altered parathyroid gland. Histological examination of postoperative material verified benign parathyroid tumors, and characteristic lesions of bone tissue were regarded as areas of osteodystrophy. Therefore, accumulation of 18F-fluorocholine at the areas of bone destruction does not enable differentiation between hyperparathyroid osteodystrophy and metastatic lesions; further research is required to assess sensitivity and specificity of the method with respect to topical diagnosis of altered parathyroid gland.

Fibrous osteodystrophy (FO), a metabolic bone disorder, has been reported in different animal species with variable susceptibility. Albeit, it is commonly reported in horses, the clinical disease is also recorded globally in goats. Diagnosis of fibrous osteodystrophy is mainly based on various clinical examination methods including biochemical alterations which can be adopted as routine diagnostic method. Therefore, the present study was aimed to investigate calcium: phosphorus (Ca:P) ratio and alkaline phosphatase (ALP) activity as biochemical diagnostic markers in goats diagnosed for fibrous osteodystrophy by clinical and radiological examinations. Blood samples were obtained from 11 goats diagnosed to have clinical fibrous osteodystrophy and 10 healthy goats, and used for harvesting serum. Goats with fibrous osteodystrophy revealed markedly elevated serum phosphorus level and ALP activity, and lowered calcium level in comparison to healthy goats. Remarkably lower serum Ca:P ratio was also observed in diseased goats. Radiological examination of skull of diseased goats revealed radio-lucent areas on the mandible as well as the upper jaw. In conclusion, marked reduction in Ca:P ratio and elevation in ALP activity could be promising biochemical diagnostic marker of fibrous osteodystrophy in goats.

The clinical phenotype of pseudohypoparathyroidism (PHP) is caused by Albright's Hereditary Osteodystrophy (AHO). Often, "round face" the only facial clinical sign reported in the literature. The aim of this study was to highlight various cranio-maxillofacial clinical findings associated with AHO.Four patients presented with PHP type 1a. Only one patient exhibited the classical round face. All patients exhibited dental anomalies, class III malocclusion with maxillary retrusion, and a copper beaten appearance of the skull. One suffered from craniosynostosis.The frequency of craniofacial and dental features associated with malocclusion should prompt careful follow-up, particularly during facial growth, in patients with AHO.

The endocrine system plays a key role in the pathogenesis of the non-infectious pathology of dairy cows. However, the role of a number of hormones in pathology is not clear. These hormones include insulin-like growth factors and leptin. The insulin-like growth factor is synthesized predominantly in the liver in response to an increase in the level of somatotropic hormone in the blood. According to its physiological properties, it is close to insulin, structurally similar, has common receptors that trigger the same chain of reactions: stimulates transport of amino acids and glucose in the muscles, increases the sensitivity of cells to insulin, in adipose tissue, transport glucose, oxidation of glucose to carbon dioxide, the inclusion of glucose in lipids. Leptin is synthesized by adipocytes, and its main physiological function is to reduce the synthesis of macroergic compounds and increase energy expenditure. Circulating in the blood, it helps to maintain an optimal level of glucose, which is necessary for the energy needs of the body. The purpose of this study was to investigate the concentration of insulin-like growth factor, leptin, glucose, pyruvate and lactate in the blood of cows under secondary osteodystrophy, ketosis and hepatodistrophy. This will give an opportunity to better understand the pathogenesis and create theoretical preconditions for the development of informative diagnostic tests and effective means of treatment. The experiment was conducted on dairy cows, analogues by age, breed, productivity and physiological state. According to clinical features, urine analysis and values of biochemical parameters of blood of experimental cows were divided into four groups: 1 – clinically healthy cows, 2 – patients with osteodystrophy, 3 – patients with ketosis, 4 – patients with hepatodistrophy. The obtained results of research indicate that the internal non-contagious pathology in dairy cows deficiency of exchange energy is recorded, which induces an increase in the activity of gluconeogenesis and is expressed by lowering the concentration of glucose and increasing the content of pyruvate and lactate. At the same time, a decrease in the level of insulin-like growth factor and leptin was found. The lowest level of insulin-like growth factor and leptin was determined by ketosis. The decrease in the level of tissue hormones in the blood plasma of cows under osteodystrophy was within the statistical error.

Introduction: Pseudohypoparathyroidism (PHP) is a rare hereditary disease, characterized by hypocalcemia/hyperphosphatemia secondary to peripheral resistance to parathyroid hormone (PTH). PHP diagnosis is usually precluded since hypocalcemia is considered as the primary diagnosis, thus delaying further diagnostic studies and preventing an adequate management of this clinical condition.Materials and methods: Retrospective review of the databases of the Endocrinology departments of two tertiary care centers of Medellin, Colombia from January 2012 to December 2016. Patients diagnosed with PHP based on clinical presentation and confirmatory laboratory values were included.Results: Four patients met the inclusion criteria. All PHP cases were diagnosed in adulthood despite strong early clinical and laboratory evidence of the disease. Three patients were diagnosed with Fahr’s syndrome and two with Albright’s hereditary osteodystrophy. The mean values obtained were PTH of 376.8 pg/mL, calcium of 6.17 mg/dL and phosphorus of 6.55 mg/dL.Conclusions: PHP is a rare disorder. This paper describes four PHP cases diagnosed during adulthood. Emphasis should be placed on the judicious approach to the patient with hypocalcemia and hyperphosphatemia with increased PTH and normal renal function, since these symptoms strongly suggest a diagnosis of PHP.

Key Clinical Message Germline loss‐of‐function GNAS mutations are associated with multiple phenotypes, depending on the parental origin of the mutant allele. Here, we describe an infantile lethal form of atypical pseudohypoparathyroidism type 1a or 1c with severe Albright's hereditary osteodystrophy phenotype, underlying the extremely variable expressivity of this syndrome.

Otosclerosis/otospongiosis is a primary osteodystrophy of the otic capsule that affects genetically predisposed individuals and leads to progressive hearing loss. Diagnosis is usually clinical, based on the findings of anamnesis, physical examination, and audiometric evaluation. However, high-resolution computed tomography scan and MRI have played an important role in the diagnosis and therapeutic approach of otosclerosis and in assisting in the differential diagnosis. The therapeutic approach is aimed at preventing, or at least minimizing, disease progression while attempting to restore hearing. The use of sodium fluoride and bisphosphonates can be an important adjunct, perhaps even primary treatment, in managing active lesions.

Background and Aims: Skeletal manifestation in liver diseases represents the minimally scrutinized part of the disease spectrum. Vitamin D deficiency has a central role in developing hepatic osteodystrophy in patients with chronic liver disease. This study aimed to investigate vitamin D levels and their relationship with disease advancement in these patients. Methods: Vitamin D levels were checked in 125 chronic liver disease patients. The patients were classified in three stages according to Child-Pugh score: A, B and C. The relationship of vitamin D levels with Child-Pugh score and other variables in the study was assessed by the contingency coefficient. Correlation and logistic regression analyses were also carried out to find additional predictors of low vitamin D levels. Results: Among the patients, 88% had either insufficient or deficient stores of vitamin D, while only 12% had sufficient vitamin D levels (p >0.05). Vitamin D levels were notably related to Child-Pugh class (contingency coefficient = 0.5, p

We examined activin receptor type IIA (ActRIIA) activation in chronic kidney disease (CKD) by signal analysis and inhibition in mice with Alport syndrome using the ActRIIA ligand trap RAP-011 initiated in 75-day-old Alport mice. At 200 days of age, there was severe CKD and associated Mineral and Bone Disorder (CKD-MBD), consisting of osteodystrophy, vascular calcification, cardiac hypertrophy, hyperphosphatemia, hyperparathyroidism, elevated FGF23, and reduced klotho. The CKD-induced bone resorption and osteoblast dysfunction was reversed, and bone formation was increased by RAP-011. ActRIIA inhibition prevented the formation of calcium apatite deposits in the aortic adventitia and tunica media and significantly decreased the mean aortic calcium concentration from 0.59 in untreated to 0.36 mg/g in treated Alport mice. Aortic ActRIIA stimulation in untreated mice increased p-Smad2 levels and the transcription of sm22α and αSMA. ActRIIA inhibition reversed aortic expression of the osteoblast transition markers Runx2 and osterix. Heart weight was significantly increased by 26% in untreated mice but remained normal during RAP-011 treatment. In 150-day-old mice, GFR was significantly reduced by 55%, but only by 30% in the RAP-011-treated group. In 200-day-old mice, the mean BUN was 100 mg/dl in untreated mice compared to 60 mg/dl in the treated group. In the kidneys of 200-day-old mice, ActRIIA and p-Smad2 were induced and MCP-1, fibronectin, and interstitial fibrosis were stimulated; all were attenuated by RAP-011 treatment. Hence, the activation of ActRIIA signaling during early CKD contributes to the CKD-MBD components of osteodystrophy and cardiovascular disease and to renal fibrosis. Thus, the inhibition of ActRIIA signaling is efficacious in improving and delaying CKD-MBD in this model of Alport syndrome.