Hip Pain in Children Yagdiran, Ayla; Zarghooni, Kourosh; Semler, Jörg Oliver ...
Deutsches Ärzteblatt international,
01/2020, Letnik:
117, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Atraumatic hip pain in children is one of the most common symptoms with which pediatricians, orthopedists, and general practitioners are confronted, with an incidence of 148 cases per 100 000 persons ...per year.
This article is based on publications up to April 2019 that were retrieved by a selective search in the PubMed data- base, including case reports and reviews.
Infants with fever often have purulent coxitis, which can be diagnosed by blood tests and ultrasonography. Toddlers and older children may suffer from painful restriction of motion of the hip joint, associated with limping (antalgic gait) or even the in- ability to walk. The main elements of the differential diagnosis in children aged 2-10 are coxitis fugax and idiopathic necrosis of the femoral head (Perthes disease). In children aged 10 and up, and in adolescents, slipped capital femoral epiphysis (SCFE) is typical. Bone tumors and rheumatic diseases must always be considered as well. The initial diagnostic steps on presentation of a child with restricted hip movement should be plain x-rays and joint ultrasonography for the detection of an effusion. Suspicion of a tumor is the main indication for tomographic imaging (computed tomography or magnetic resonance imaging).
The underlying cause of hip pain in children should be diagnosed early to avoid adverse sequelae.
Zusammenfassung
Ein Merkmal der Pubertät ist die schnelle Zunahme der Körperhöhe, die insbesondere durch ein rasantes Längenwachstum der Röhrenknochen, aber auch der Wirbelsäule gekennzeichnet ist. ...Um eine ausreichende Stabilität des Skelettsystems auch in Phasen schnellen Längenwachstums zu gewährleisten, bedarf es eng abgestimmter Einflussfaktoren, die die Knochenaufbau- und -umbauvorgänge steuern. Die Muskulatur gilt dabei als der entscheidende osteoanabole Stimulus über die funktionelle Muskel-Knochen-Einheit. Aber auch hormonelle Einflussfaktoren und ein ausreichendes Angebot von Mineralien sind unabdingbar für das Wachstum und die Adaptation der Knochen an die jeweilige Beanspruchung und das Wachstumsverhalten. In der Pubertät nimmt der Einfluss der Sexualhormone auf den Knochenstoffwechsel zu. Der Aufbau von Knochenmasse erfolgt bei Jungen periostal in Assoziation zur testosterongesteuerten Muskelzunahme, bei Mädchen vor allem endostal durch den Östrogenanstieg, der die Osteoklasten am Knochenabbau hindert. Das pathophysiologische Verständnis bildet die Grundlage der zielgerichteten Therapie bzw. Entwicklung eines individuellen Versorgungskonzepts im Falle einer reduzierten Knochengesundheit, wie sie beispielsweise im Rahmen von Hormonmangelsituationen bei Pubertätsstörungen oder Essstörungen auftritt. Eine generelle Empfehlung zum Einsatz von oralen Kontrazeptiva in Hormonmangelsituationen als „Knochenschutz“ liegt nicht vor. Im Falle eines Hypogonadismus sollte der differenzierte Einsatz einer Hormonersatztherapie hinsichtlich der skeletalen Situation gemäß aktueller Evidenzlage individuell mit den Betroffenen abgewogen werden. Insbesondere im Pubertätsalter kann so die Basis einer lang anhaltenden Knochengesundheit gelegt werden.
As a result of a whole-exome sequencing study, we report three mutant alleles in SEC24D, a gene encoding a component of the COPII complex involved in protein export from the ER: the truncating ...mutation c.613C>T (p.Gln205∗) and the missense mutations c.3044C>T (p.Ser1015Phe, located in a cargo-binding pocket) and c.2933A>C (p.Gln978Pro, located in the gelsolin-like domain). Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles, with c.3044C>T being embedded in a 14 Mb founder haplotype shared by all three. The affected individuals were a 7-year-old boy with a phenotype most closely resembling Cole-Carpenter syndrome and two fetuses initially suspected to have a severe type of osteogenesis imperfecta. All three displayed a severely disturbed ossification of the skull and multiple fractures with prenatal onset. The 7-year-old boy had short stature and craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures. Electron and immunofluorescence microscopy of skin fibroblasts of this individual revealed that ER export of procollagen was inefficient and that ER tubules were dilated, faithfully reproducing the cellular phenotype of individuals with cranio-lentico-sutural dysplasia (CLSD). CLSD is caused by SEC23A mutations and displays a largely overlapping craniofacial phenotype, but it is not characterized by generalized bone fragility and presented with cataracts in the original family described. The cellular and morphological phenotypes we report are in concordance with the phenotypes described for the Sec24d-deficient fish mutants vbi (medaka) and bulldog (zebrafish).
Osteogenesis imperfecta (OI) is a rare disease leading to hereditary bone fragility. Nearly 90% of cases are caused by mutations in the collagen genes COL1A1/A2 (classical OI) leading to multiple ...fractures, scoliosis, short stature and nonskeletal findings as blue sclera, hypermobility of joints, bone pain and delayed motor function development. Bisphosphonates are used in most moderate and severely affected patients assuming that an increase of bone mineral density might reduce fractures and bone pain in patients with OI. Denosumab as a RANK ligand antibody inhibiting osteoclast maturation has been approved for osteoporosis treatment in adults. First data from small clinical trials promised a high efficacy of Denosumab in children with OI. Aim of this analysis was a retrospective evaluation of an individualized biomarker-associated treatment regime with Denosumab in 10 children with classical OI which were followed for 1 year after their participation in a pilot trial with Denosumab. Therefore urinary deoxypyridinoline levels were evaluated frequently as an osteoclastic activity marker and depending on that levels Denosumab injections were scheduled individually.
Ten patients (age range: 6.16-12.13 years; all participated in the former OI-AK phase 2 trial (NCT01799798)) were included in the follow-up period. Denosumab was administered subcutaneously depending on the individual urinary excretion course of deoxypyridinoline (DPD/Crea) as osteoclastic activity marker with 1 mg/kg body weight. DPD/Crea levels were evaluated before denosumab administration and afterwards. If patients present after an initial decrease after injection with a re-increase up to the DPD/crea level before Denosumab injection next dosage was planned. Changes of areal bone mineral density (aBMD) using dual energy x-ray absorptiometry of the lumbar spine after 12 month was evaluated. Safety was assessed by bone metabolism markers and side effect reporting.
During follow-up mean relative change of lumbar aBMD was - 6.4%. Lumbar spine aBMD z-Scores decreased from - 1.01 ± 2.61 (mean ± SD) to - 1.91 ± 2.12 (p = 0.015). Mobility changed not significantly (GMFM-88 -6.49 ± 8.85% (p = 0.08). No severe side effects occurred. Dose intervals could be extended in the mean from 12 weeks previously to 20.3 weeks.
On average, it was possible to prolong the intervals between drug administrations and to reduce the total dose about by 25% without a decrease of mobility or change of vertebral shape despite a reduction of lumbar aBMD during 1 year of biomarker-directed Denosumab treatment. Further trials are necessary to balance side effects and highest efficacy in children.
The IMPACT survey aimed to elucidate the humanistic, clinical and economic burden of osteogenesis imperfecta (OI) on individuals with OI, their families, caregivers and wider society. Research ...methodology, demographics and initial insights from the survey have been previously reported. The cost of illness (healthcare resource use, productivity loss, out-of-pocket spending) and drivers of the economic impact of OI are reported here. IMPACT was an international mixed-methods online survey in eight languages (fielded July-September 2021) targeting adults (aged greater than or equal to 18 years) or adolescents (aged greater than or equal to 12-17 years) with OI, caregivers with or without OI and other close relatives. Survey domains included demographics, socioeconomic factors, clinical characteristics, treatment patterns, quality of life and health economics. The health economic domain for adults, which included questions on healthcare resource use, productivity loss and out-of-pocket spending, was summarised. Regression and pairwise analyses were conducted to identify independent drivers and associations with respondent characteristics. Overall, 1,440 adults with OI responded to the survey. Respondents were mostly female (70%) and from Europe (63%) with a median age of 43 years. Within a 12-month period, adults with OI reported visiting a wide range of healthcare professionals. Two-thirds (66%) of adults visited a hospital, and one-third (33%) visited the emergency department. The mean total number of diagnostic tests undergone by adults within these 12 months was 8.0. Adults had undergone a mean total of 11.8 surgeries up to the time point of the survey. The proportions of adults using queried consumables or services over 12 months ranged from 18-82%, depending on the type of consumable or service. Most adults (58%) were in paid employment, of which nearly one-third (29%) reported missing a workday. Of the queried expenses, the mean total out-of-pocket spending in 4 weeks was euro191. Respondent characteristics such as female sex, more severe self-reported OI and the experience of fractures were often associated with increased economic burden. IMPACT provides novel insights into the substantial cost of illness associated with OI on individuals, healthcare systems and society at large. Future analyses will provide insights into country-specific economic impact, humanistic impact and the healthcare journey of individuals with OI.
Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and susceptibility to fractures after minimal trauma. After mutations in all known OI genes had been ...excluded by Sanger sequencing, we applied next-generation sequencing to analyze the exome of a single individual who has a severe form of the disease and whose parents are second cousins. A total of 26,922 variations from the human reference genome sequence were subjected to several filtering steps. In addition, we extracted the genotypes of all dbSNP130-annotated SNPs from the exome sequencing data and used these 299,494 genotypes as markers for the genome-wide identification of homozygous regions. A single homozygous truncating mutation, affecting
SERPINF1 on chromosome 17p13.3, that was embedded into a homozygous stretch of 2.99 Mb remained. The mutation was also homozygous in the affected brother of the index patient. Subsequently, we identified homozygosity for two different truncating
SERPINF1 mutations in two unrelated patients with OI and parental consanguinity. All four individuals with
SERPINF1 mutations have severe OI. Fractures of long bones and severe vertebral compression fractures with resulting deformities were observed as early as the first year of life in these individuals. Collagen analyses with cultured dermal fibroblasts displayed no evidence for impaired collagen folding, posttranslational modification, or secretion.
SERPINF1 encodes pigment epithelium-derived factor (PEDF), a secreted glycoprotein of the serpin superfamily. PEDF is a multifunctional protein and one of the strongest inhibitors of angiogenesis currently known in humans. Our data provide genetic evidence for PEDF involvement in human bone homeostasis.
Summary Background Children with osteogenesis imperfecta are often treated with intravenous bisphosphonates. We aimed to assess the safety and efficacy of risedronate, an orally administered ...third-generation bisphosphonate, in children with the disease. Methods In this multicentre, randomised, parallel, double-blind, placebo-controlled trial, children aged 4–15 years with osteogenesis imperfecta and increased fracture risk were randomly assigned by telephone randomisation system in a 2:1 ratio to receive either daily risedronate (2·5 or 5 mg) or placebo for 1 year. Study treatment was masked from patients, investigators, and study centre personnel. Thereafter, all children received risedronate for 2 additional years in an open-label extension. The primary efficacy endpoint was percentage change in lumbar spine areal bone mineral density (BMD) at 1 year. The primary efficacy analysis was done by ANCOVA, with treatment, age group, and pooled centre as fixed effects, and baseline as covariate. Analyses were based on the intention-to-treat population, which included all patients who were randomly assigned and took at least one dose of assigned study treatment. The trial is registered with ClinicalTrials.gov , number NCT00106028. Findings Of 147 patients, 97 were randomly assigned to the risedronate group and 50 to the placebo group. Three patients from the risedronate group and one from the placebo group did not receive study treatment, leaving 94 and 49 in the intention-to-treat population, respectively. The mean increase in lumbar spine areal BMD after 1 year was 16·3% in the risedronate group and 7·6% in the placebo group (difference 8·7%, 95% CI 5·7–11·7; p<0·0001). After 1 year, clinical fractures had occurred in 29 (31%) of 94 patients in the risedronate group and 24 (49%) of 49 patients in the placebo group (p=0·0446). During years 2 and 3 (open-label phase), clinical fractures were reported in 46 (53%) of 87 patients in the group that had received risedronate since the start of the study, and 32 (65%) of 49 patients in the group that had been given placebo during the first year. Adverse event profiles were otherwise similar between the two groups, including frequencies of reported upper-gastrointestinal and selected musculoskeletal adverse events. Interpretation Oral risedronate increased areal BMD and reduced the risk of first and recurrent clinical fractures in children with osteogenesis imperfecta, and the drug was generally well tolerated. Risedronate should be regarded as a treatment option for children with osteogenesis imperfecta. Funding Alliance for Better Bone Health (Warner Chilcott and Sanofi).
The importance of patient centricity and keeping the patient at the heart of research design is now well recognised within the healthcare community. The involvement of patient, caregiver and ...clinician representatives in the study design process may help researchers to achieve this goal and to ensure robust and meaningful data generation. Real-world data collection allows for a more flexible and patient-centred research approach for gaining important insights into the experience of disease and treatments, which is acutely relevant for rare diseases where knowledge about the disease is more likely to be limited. Here, we describe a practical example of a patient-centric, multi-stakeholder approach that led to the co-design of a prospective observational study investigating the lived experience of adolescents with the rare disease, X-linked hypophosphataemia. Specifically, we describe how the knowledge and expertise of a diverse research team, which included expert physicians, research and technology specialists, patients and caregivers, were applied in order to identify the relevant research questions and to ensure the robustness of the study design and its appropriateness to the population of interest within the context of the current clinical landscape. We also demonstrate how a structured patient engagement exercise was key to informing the selection of appropriate outcome measures, data sources, timing of data collection, and to assessing the feasibility and acceptability of the proposed data collection approach.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
On the occasion of the 13th International Conference on Osteogenesis imperfecta in August 2017 an expert panel was convened to develop an international consensus paper regarding physical ...rehabilitation in children and adolescents with Osteogenesis imperfecta. The experts were chosen based on their clinical experience with children with osteogenesis imperfecta and were identified by sending out questionnaires to specialized centers and patient organizations in 26 different countries. The final expert-group included 16 representatives (12 physiotherapists, two occupational therapists and two medical doctors) from 14 countries. Within the framework of a collation of personal experiences and the results of a literature search, the participating physiotherapists, occupational therapists and medical doctors formulated 17 expert-statements on physical rehabilitation in patients aged 0-18 years with osteogenesis imperfecta.
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