Case Report: Multiple Fractures in a Patient with Mutations of TWIST1 and TNSALP

Hypophosphatasia is a rare inherited disorder characterized by defective skeletal mineralization and low alkaline phosphatase activities in the serum. The genetic cause of hypophosphatasia is believed related to inactivating mutations in the TNSALP gene, encoding tissue-nonspecific alkaline phosphatase. Another rare inheritable disease, Saethre-Chotzen syndrome, leads to premature fusion of the cranial sutures caused by heterozygous mutations of the human TWIST1 gene. Because the two disorders apparently are not genetically related (only reported individually) yet both involve defective skeletal formation, we believe it is important to report our findings on a patient harboring mutations of TNSALP and TWIST1

Prevalence of low alkaline phosphatase activity in laboratory assessment: Is hypophosphatasia an underdiagnosed disease?

Background!#!Tissue-nonspecific alkaline phosphatase (TNSALP) encoded by the ALPL gene is of particular importance for bone mineralization. Mutation in the ALPL gene can lead to persistent low ALP activity resulting in the rare disease Hypophosphatasia (HPP) that is characterized by disturbed bone and dental mineralization. While severe forms are extremely rare with an estimated prevalence of 1/100.000, recent studies suggest that moderate form caused by heterozygous mutations are much more frequent with an estimated prevalence of 1/508. The purpose of this study was to estimate the prevalence of low AP levels in the population based on laboratory measurements.!##!Methods!#!In this study, the prevalence of low AP activity and elevated pyridoxal-5-phosphate (PLP) levels was analyzed in 6.918.126 measurements from 2011 to 2016 at a single laboratory in northern Germany. Only laboratory values of subjects older than 18 years of age were included. Only the first measurement was included, all repeated values were excluded.!##!Results!#!In total, 8.46% of the measurements of a total of 6.918.126 values showed a value < 30 U/L. 0.59% of the subjects with an ALP activity below 30 U/L had an additional PLP measurement. Here, 6.09% showed elevated pyridoxal-5-phosphate (PLP) levels. This suggest that 0.52% (1:194) of subjects show laboratory signs of HPP.!##!Conclusion!#!These data support the genetic estimation that the prevalence of moderate forms of HPP may be significantly higher than expected. Based on these data, we recommend automatically measurement of PLP in the case of low ALP activity and a notification to the ordering physician that HPP should be included in the differential diagnosis and further exploration is recommended

Identification of vitamin D and other bone metabolism parameters as risk factors for primary bone marrow oedema syndrome

Abstract Background The aetiology and pathogenesis of primary bone marrow oedema syndrome (BMES) remain unclear. This retrospective cross-sectional study in a large cohort of patients with BMES was performed to characterise the overall skeletal status and turnover in patients with BMES, with the aim of identifying risk factors for this disease. Methods Patients who were diagnosed with BMES on the basis of clinical and radiological (magnetic resonance imaging) findings in our outpatient clinic were identified retrospectively. Patient history, co-existing metabolic disorders, bone metabolism parameters (serum calcium, phosphate, 25-OH-D3, bone-specific alkaline phosphatase, parathyroid hormone, and osteocalcin, and urinary deoxypyridinoline) and bone mineral density (as measured by dual-energy X-ray absorptiometry) were extracted from the medical records. Patients with secondary causes for BMES were excluded from the study. Results Of the 171 patients, 65 were identified without secondary cause for BMES. Of the 65 patients, 61.5% were female. The mean age was 49.5 ± 16.7 years, and age-related BMES prevalence showed two peaks, one in adolescence (11–20 years) and one at an older age (51–70 years). BMES predominantly affected the weight-bearing joints, namely, the ankle/foot (55.1%), knee (22.4%) and proximal femur (16.3%). Thyroid disorders and secondary hyperparathyroidism were highly prevalent (21.5 and 21.4%, respectively). On average, the cohort had elevated deoxypyridinoline levels and low 25-OH-D3 levels (19.0 ± 7.5 μg/l in patients without vitamin D supplementation). Osteopenia and osteoporosis were diagnosed in 47.4 and 17.5% of patients, respectively. Conclusions BMES is associated with high bone turnover. Patients who are diagnosed with BMES should be screened carefully for bone metabolism disorders and their potential risk factors

Current structure of care and treatment options for patients with rare bone diseases at University Hospitals in Germany

Medical care for patients with Rare Bone and Mineral conditions (RBMC) require lifelong, multidisciplinary efforts including different subspecialties such as endocrinology, nephrology, orthopaedics, rheumatology, radiology, cardiology, neurology, internal medicine, paediatrics and clinical genetics. National networking and local organization and management of care in RBMC is of central importance and was assessed by means of a national survey. The aim of the study was to identify and characterize the services, organisation and existing expertise concerning RBMC at University Hospitals in Germany. All 32 Centers for Rare Diseases (ZSE) at German University Hospitals were contacted with a questionnaire in 2018. Of those, 15 centers took part in the survey, resulting in a response rate of 47%. The responses revealed differences most pronounced in the level of equipment and diagnostic capabilities. While most centers had implemented tools for patient empowerment, only few centers were involved in research activities in RBMC or offered structured training programs for physicians and medical students. The results of the survey can be helpful to initiate concrete action plans to improve healthcare for patients with RBMC in Germany

Treatments for Hypophosphatasia

Hypophosphatasia due to genetically determined deficient activity of the tissue non-specific alkaline phosphatase (TNAP) is characterized by a wide spectrum of potential clinical manifestations, both, regarding the type of symptoms, as well as the severity of associated deficits. Appropriate treatment strategies should be built on a multimodal approach specifically considering individual disease manifestation. For patients with disease onset before adulthood, enzyme replacement therapy with Asfotase alfa (Strensiq) is approved in Europe to treat the bone manifestation of the disease. Both, available data from clinical trials as well as clinical routine experience confirm basically encouraging results of that treatment in severely affected children with substantial improvement regarding radiographic and functional outcome parameters as well as overall survival. Even in adult patients with severe disease manifestation pursuant to the approval, first results confirm substantial amelioration of disease-specific deficits and functional improvements. Meanwhile, there is also data supporting safety and efficacy of long-term treatment Asfotase alfa over several years. While inflammatory pain, which is typically perceived as being burdensome, can commonly be addressed successfully with NSAIDs on-demand, overall musculoskeletal health requires sustained, multimodal, supportive treatment strategies including exercise interventions as well as age and health state adjusted technical orthopedic support. The use and potential clinical impact of Phosphate and Vitamin B6 on the course of the disease requires further investigation. Current data regarding the use of bone-targeted compounds is critical in terms of antiresorptives while osteoanabolic treatment strategies appear feasible. Ideally, the entirety of therapeutic measures should be coordinated and overlooked at an experienced center while individual tasks can preferably be accomplished at local facilities near the patient's home

Denosumab and surgery for the treatment of Perthes’ disease in a 9-year-old boy: favorable course documented by comprehensive imaging— a case report

Denosumab and surgery for the treatment of Perthes’ disease in a 9-year-old boy: favorable course documented by comprehensive imaging— a case repor

Intra-articular osteoid osteoma accompanied by extensive bone marrow edema. A clinical and micro-morphological analysis

Osteoid osteoma (OO) is a benign bone tumor producing non-mineralized bone matrix (i.e., osteoid). While peritumoral edema is commonly found in OO, extensive bone marrow edema has been reported less frequently. Furthermore, the micro-morphological characteristics of the nidus and its central calcification remain unclear. In this study, a consecutive series of four patients suffering from extensive bone marrow edema triggered by intra-articular osteoid osteoma underwent clinical examination, magnetic resonance imaging (MRI) and computed tomography (CT) as well as dual-energy X-ray absorptiometry (DXA) and laboratory bone turnover analyses. The obtained resection specimens were processed by undecalcified histology and were subsequently analyzed by light microscopy and quantitative backscattered electron imaging (qBEI). We report an entity of intra-articular osteoid osteoma in the knee and foot, in which an extensive and persistent bone marrow edema syndrome masked the correct diagnosis. While metabolic bone diseases were excluded in all cases, the reassessment of the patients' clinical history including pain characteristics (nocturnal, aspirin sensitivity) led us to perform additional CT, where the tumor was diagnosed. The micro-morphological analysis of the OO biopsies revealed that the nidus was surrounded by hyperosteoidosis, while central mineralization was detected in all cases. This mineralized area showed a significantly higher mineralization heterogeneity than the surrounding trabecular bone and more disorganized collagen fibers detected by qBEI and polarized light microscopy, respectively. Taken together, our results indicate that osteoid osteoma should be considered when persistent and extensive, periarticular bone marrow edema is diagnosed. The central calcification that is found inside the nidus in conventional imaging was mirrored by bone matrix with a heterogeneous mineralization pattern

A retrospective analysis of bone mineral status in patients requiring spinal surgery

Abstract Background Impaired bone quality is associated with poor outcome of spinal surgery. The aim of the study was to assess the bone mineral status of patients scheduled to undergo spinal surgery and to report frequencies of bone mineral disorders. Methods We retrospectively analyzed the bone mineral status of 144 patients requiring spinal surgery including bone mineral density by dual-energy X-ray absorptiometry (DXA) as well as laboratory data with serum levels of 25-hydroxyvitamin D (25-OH-D), parathyroid hormone, calcium, bone specific alkaline phosphate, osteocalcin, and gastrin. High-resolution peripheral quantitative computed tomography (HR-pQCT) was additionally performed in a subgroup of 67 patients with T-Score below − 1.5 or history of vertebral fracture. Results Among 144 patients, 126 patients (87.5%) were older than 60 years. Mean age was 70.1 years. 42 patients (29.1%) had suffered from a vertebral compression fracture. 12 previously undiagnosed vertebral deformities were detected in 12 patients by vertebral fracture assessment (VFA). Osteoporosis was present in 39 patients (27.1%) and osteopenia in 63 patients (43.8%). Only 16 patients (11.1%) had received anti-osteoporotic therapy, while 54 patients (37.5%) had an indication for specific anti-osteoporotic therapy but had not received it yet. The majority of patients had inadequate vitamin D status (73.6%) and 34.7% of patients showed secondary hyperparathyroidism as a sign for a significant disturbed calcium homeostasis. In a subgroup of 67 patients, severe vertebral deformities were associated with stronger deficits in bone microarchitecture at the distal radius compared to the distal tibia. Conclusions This study shows that bone metabolism disorders are highly prevalent in elderly patients scheduled for spinal surgery. Vertebral deformities are associated with a predominant deterioration of bone microstructure at the distal radius. As impaired bone quality can compromise surgical outcome, we strongly recommend an evaluation of bone mineral status prior to operation and anti-osteoporotic therapy if necessary