Pediatric computed tomography doses in Germany from 2016 to 2018 based on large-scale data collection.

PURPOSE: Accumulating evidence from epidemiological studies that pediatric computed tomography (CT) examinations can be associated with a small but non-zero excess risk for developing leukemia or brain tumor highlights the need to optimize doses of pediatric CT procedures. Mandatory dose reference levels (DRL) can support reduction of collective dose from CT imaging. Regular surveys of applied dose-related parameters are instrumental to decide when technological advances and optimized protocol design allow lower doses without sacrificing image quality. Our aim was to collect dosimetric data to support adapting current DRL to changing clinical practice. METHOD: Dosimetric data and technical scan parameters from common pediatric CT examinations were retrospectively collected directly from Picture Archiving and Communication Systems (PACS), Dose Management Systems (DMS), and Radiological Information Systems (RIS). RESULTS: We collected data from 17 institutions on 7746 CT series from the years 2016 to 2018 from examinations of the head, thorax, abdomen, cervical spine, temporal bone, paranasal sinuses and knee in patients below 18 years of age. Most of the age-stratified parameter distributions were lower than distributions from previously-analyzed data from before 2010. Most of the third quartiles were lower than German DRL at the time of the survey. CONCLUSIONS: Directly interfacing PACS, DMS, and RIS installations allows large-scale data collection but relies on high data-quality at the documentation stage. Data should be validated by expert knowledge or guided questionnaires. Observed clinical practice in pediatric CT imaging suggests lowering some DRL in Germany is reasonable.

Efficacy and Feasibility of Proton Beam Therapy in Relapsed High-Risk Neuroblastoma-Experiences from the Prospective KiProReg Registry.

BACKGROUND: Despite an intensive multimodal treatment approach, approximately 50% of high-risk (HR) neuroblastoma (NB) patients experience progression. Despite the advances in targeted therapy, high-dose chemotherapy, and other systemic treatment options, radiation therapy (RT) to sites of relapsed disease can be an option to reduce tumor burden and improve chance for disease control. METHODS: Patients who received salvage irradiation with proton beam therapy (PBT) for local or metastatic relapse of HR NB within the prospective registry trials KiProReg and ProReg were eligible for this retrospective analysis. Data on patient characteristics, multimodality therapy, adverse events, and oncologic endpoints were evaluated. Adverse events were assessed before, during, and after PBT according to common terminology criteria for adverse events (CTCAE) V4.0. RESULTS: Between September 2013 and September 2020, twenty (11 male; 9 female) consecutive patients experiencing local (N = 9) or distant recurrence (N = 25) were identified for this analysis. Distant recurrences included osteomedullary (N = 11) or CNS lesions (N = 14). Salvage therapy consisted of re-induction chemo- or chemo-immuno-therapy (N = 19), surgery (N = 6), high-dose chemotherapy and stem cell transplantation (N = 13), radiation (N = 20), and concurrent systemic therapy. Systemic therapy concurrent to RT was given to six patients and included temozolomide (N = 4), carboplatine (N = 1), or anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKI) (N = 1). A median dose of 36 Gy was applied to the 34 recurrent sites. Local RT was applied to 15 patients, while five patients, received craniospinal irradiation for CNS relapse. After a median follow-up (FU) of 20 months (4-66), the estimated rate for local control, distant metastatic free survival, and overall survival at 3 years was 68.0%, 37.9%, and 61.6%, respectively. During RT, ten patients (50%) presented with a higher-grade acute hematologic adverse event. Late higher-grade sequelae included transient myelitis with transverse section (N = 2) and secondary malignancy outside of the RT field (N = 1). CONCLUSION: Our study demonstrates the efficacy and safety of RT/PBT for recurrent HR NB in a multimodality second-line approach. To better define the role of RT for these patients, prospective studies would be desirable.

Proton Beam Therapy for Children With Neuroblastoma: Experiences From the Prospective KiProReg Registry.

OBJECTIVE: Radiotherapy (RT) is an integral part of the interdisciplinary treatment of patients with high-risk neuroblastoma (NB). With the continuous improvements of outcome, the interest in local treatment strategies that reduce treatment-related side effects while achieving optimal oncological results is growing. Proton beam therapy (PBT) represents a promising alternative to conventional photon irradiation with regard to the reduction of treatment burden. METHOD: Retrospective analysis of children with high or intermediate risk NB receiving PBT of the primary tumor site during first-line therapy between 2015 and 2020 was performed. Data from the prospective in-house registry Standard Protonentherapie WPE - Kinder- (KiProReg) with respect to tumor control and treatment toxicity were analyzed. Adverse events were classified according to CTCAE Version 4 (V4.0) before, during, and after PBT. RESULTS: In total, 44 patients (24 male, 20 female) with high (n = 39) or intermediate risk NB (n = 5) were included in the analysis. Median age was 3.4 years (range, 1.4-9.9 years). PBT doses ranged from 21.0 to 39.6 Gray (Gy) (median 36.0 Gy). Five patients received PBT to the MIBG-avid residual at the primary tumor site at time of PBT according to the NB-2004 protocol. In 39 patients radiation was given to the pre-operative tumor bed with or without an additional boost in case of residual tumor. After a median follow-up (FU) of 27.6 months, eight patients developed progression, either local recurrence (n = 1) or distant metastases (n = 7). Four patients died due to tumor progression. At three years, the estimated local control, distant metastatic free survival, progression free survival, and overall survival was 97.7, 84.1, 81.8, and 90.9%, respectively. During radiation, seven patients experienced higher-grade (CTCAE ≥ °3) hematologic toxicity. No other higher grade acute toxicity occurred. After PBT, one patient developed transient myelitis while receiving immunotherapy. No higher grade long-term toxicity was observed up to date. CONCLUSION: PBT was a well tolerated and effective local treatment in children with high and intermediate risk NB. The role of RT in an intensive multidisciplinary treatment regimen remains to be studied in the future in order to better define timing, doses, target volumes, and general need for RT in a particularly sensitive cohort of patients.

A novel mutation in sphingosine-1-phosphate lyase causing congenital brain malformation.

INTRODUCTION: Recently recessive mutations in sphingosine-1-phosphate lyase (SGPL1) have been published as a cause of syndromic congenital nephrotic syndrome with adrenal insufficiency. We have identified a case with fetal hydrops and brain malformations due to a mutation in SGPL1. CASE REPORT: We report a patient presenting with severe fetal hydrops, congenital nephrotic syndrome and adrenal calcifications. MRI imaging showed generalized cortical atrophy with simplified gyral pattern and hypoplastic temporal lobes as well as cerebellar hypoplasia and hyperintensity in the pons. The boy deceased at 6 weeks of age. Via whole exome sequencing, we identified a novel homozygous frameshift mutation c.1233delC (p.Phe411Leufs∗56) in SGPL1. CONCLUSION: In our patient, we describe a novel mutation in sphingosine-1-phosphate lyase (SGPL1) leading to severe brain malformation. Neurodevelopmental phenotypes have been reported earlier, but not described in detail. To this end, we present a review on all published SGPL1-mutations and genotype-phenotype correlations focusing on neurodevelopmental outcomes. We hypothesized on the severe neurological phenotypes, which might be due to disruption of neuronal autophagy. Mutations in SGPL1 shall be considered in the differential diagnosis of fetal hydrops as well as congenital brain malformations and neuropathies.

Magnetic resonance T2 mapping and diffusion-weighted imaging for early detection of cystogenesis and response to therapy in a mouse model of polycystic kidney disease.

Polycystic kidney disease (PKD) is among the leading causes of end-stage renal disease. Increasing evidence exists that molecular therapeutic strategies targeted to cyst formation and growth might be more efficacious in early disease stages, highlighting the growing need for sensitive biomarkers. Here we apply quantitative magnetic resonance imaging techniques of T2 mapping and diffusion-weighted imaging in the jck mouse model for PKD using a clinical 3.0 T scanner. We tested whether kidney T2 values and the apparent diffusion coefficient (ADC) are superior to anatomical imaging parameters in the detection of early cystogenesis, as shown on macro- and histopathology. We also tested whether kidney T2 values and ADC have the potential to monitor early treatment effects of therapy with the V2 receptor antagonist Mozavaptane. Kidney T2 values and to a lesser degree ADC were found to be highly sensitive markers of early cystogenesis and superior to anatomical-based imaging parameters. Furthermore, kidney T2 values exhibited a nearly perfect correlation to the histological cystic index, allowing a clear separation of the two mouse genotypes. Additionally, kidney T2 values and ADC were able to monitor early treatment effects in the jck mouse model in a proof-of-principle experiment. Thus, given the superiority of kidney T2 values and ADC over anatomical-based imaging in mice, further studies are needed to evaluate the translational impact of these techniques in patients with PKD.

Ultrasound-guided percutaneous renal biopsy in 295 children and adolescents: role of ultrasound and analysis of complications.

INTRODUCTION: Percutaneous renal biopsy (PRB) is a decisive diagnostic procedure for children and adolescents with renal diseases. Aim of this study was to evaluate retrospectively the complication rates of percutaneous kidney biopsies and their therapeutic consequences to assess the role of ultrasound-guidance including Doppler ultrasound examinations in preparation, execution and follow-up care and to present a recommended protocol. PATIENTS AND METHODS: Institutional review board approved this retrospective study; informed consent was waived. Between 1997 and 2011 a total of 438 ultrasound-guided biopsies were performed in 295 patients, 169 of the biopsies were performed on kidney transplants. Average age of patients was 10.2+/-5.2 years (range of 15 days until age of 23). Before and post biopsy ultrasound examination including Doppler examination was carried out. Biopsy itself was ultrasound monitored. Complications were analysed with regard to age of patient, kidney transplants, year of occurrence, number of punctures, performing physician and time interval of occurrence to develop an optimized protocol for ultrasound-guidance. RESULTS: In 99% of cases successful PRB were performed, i.e. enough kidney parenchyma for histological analysis was obtained. No lethal or major complication that required surgical intervention occurred. Eighteen relevant complications were observed (complication rate: 4.1%). Except in one case in which additional MRI diagnostic was necessary, ultrasound examination after 4 hours post biopsy or even earlier when symptoms occurred, was able to detect complications and determine indications for intervention. CONCLUSION: Ultrasound-guided PRB is an established and effective method in children and adolescents, but shows a certain rate of complications and therefore should not be indicated without diligence. Ultrasound including Doppler ultrasound is a valuable tool in preparation, guidance of biopsy, detection of complications and in follow-up care. Ultrasound examinations (including Doppler) pre-, during and 4 hours post kidney biopsy and, depending from case, a few days until weeks after biopsy is recommended.

Two years' experience with denosumab for children with osteogenesis imperfecta type VI.

BACKGROUND: Osteogenesis imperfecta (OI) is a hereditary disease causing reduced bone mass, increased fracture rate, long bone deformities and vertebral compressions. Additional non skeletal findings are caused by impaired collagen function and include hyperlaxity of joints and blue sclera. Most OI cases are caused by dominant mutations in COL1A1/2 affecting bone formation. During the last years, recessive forms of OI have been identified, mostly affecting posttranslational modification of collagen. In 2011, mutations in SERPINF1 were identified as the molecular cause of OI type VI, and thereby a novel pathophysiology of the disease was elucidated. The subgroup of patients with OI type VI are affected by an increased bone resorption, leading to the same symptoms as observed in patients with an impaired bone formation. Severely affected children are currently treated with intravenous bisphosphonates regardless of the underlying mutation and pathophysiology. Patients with OI type VI are known to have a poor response to such a bisphosphonate treatment. METHOD: Deciphering the genetic cause of OI type VI in our 4 patients (three children and one adolescent) led to an immediate translational approach in the form of a treatment with the monoclonal RANKL antibody Denosumab (1 mg/kg body weight every 12 weeks). RESULTS: Short-term biochemical response to this treatment was reported previously. We now present the results after 2 years of treatment and demonstrate a long term benefit as well as an increase of bone mineral density, a normalization of vertebral shape, an increase of mobility, and a reduced fracture rate. CONCLUSION: This report presents the first two-year data of denosumab treatment in patients with Osteogenesis imperfecta type VI and in Osteogenesis imperfecta in general as an effective and apparently safe treatment option.

Mutation of POC1B in a severe syndromic retinal ciliopathy.

We describe a consanguineous Iraqi family with Leber congenital amaurosis (LCA), Joubert syndrome (JBTS), and polycystic kidney disease (PKD). Targeted next-generation sequencing for excluding mutations in known LCA and JBTS genes, homozygosity mapping, and whole-exome sequencing identified a homozygous missense variant, c.317G>C (p.Arg106Pro), in POC1B, a gene essential for ciliogenesis, basal body, and centrosome integrity. In silico modeling suggested a requirement of p.Arg106 for the formation of the third WD40 repeat and a protein interaction interface. In human and mouse retina, POC1B localized to the basal body and centriole adjacent to the connecting cilium of photoreceptors and in synapses of the outer plexiform layer. Knockdown of Poc1b in zebrafish caused cystic kidneys and retinal degeneration with shortened and reduced photoreceptor connecting cilia, compatible with the human syndromic ciliopathy. A recent study describes homozygosity for p.Arg106ProPOC1B in a family with nonsyndromic cone-rod dystrophy. The phenotype associated with homozygous p.Arg106ProPOC1B may thus be highly variable, analogous to homozygous p.Leu710Ser in WDR19 causing either isolated retinitis pigmentosa or Jeune syndrome. Our study indicates that POC1B is required for retinal integrity, and we propose POC1B mutations as a probable cause for JBTS with severe PKD.

Mutations in WNT1 cause different forms of bone fragility.

We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures. In consanguineous families, we identified five homozygous mutations in WNT1: one frameshift mutation, two missense mutations, one splice-site mutation, and one nonsense mutation. In addition, in a family affected by dominantly inherited early-onset osteoporosis, a heterozygous WNT1 missense mutation was identified in affected individuals. Initial functional analysis revealed that altered WNT1 proteins fail to activate canonical LRP5-mediated WNT-regulated ß-catenin signaling. Furthermore, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development. Our finding that homozygous and heterozygous variants in WNT1 predispose to low-bone-mass phenotypes might advance the development of more effective therapeutic strategies for congenital forms of bone fragility, as well as for common forms of age-related osteoporosis.

Liver cell transplantation in severe infantile oxalosis--a potential bridging procedure to orthotopic liver transplantation?

BACKGROUND: The infantile form of primary hyperoxaluria type I (PHI) is the most devastating PH subtype leading to early end-stage renal failure and severe systemic oxalosis. Combined or sequential liver-kidney transplantation (LKTx) is the only curative option but it involves substantial risks, especially in critically ill infants. The procedure also requires resources that are simply not available to many children suffering from PHI worldwide. Less invasive and less complex therapeutic interventions allowing a better timing are clearly needed. Liver cell transplantation (LCT) may expand the narrow spectrum of auxiliary measures to buy time until LKTx for infants can be performed more safely. METHODS: We performed LCT (male neonate donor) in a 15-month-old female in reduced general condition suffering from systemic oxalosis. Renal replacement therapy, initiated at the age of 3 months, was complicated by continuous haemodialysis access problems. Living donor liver transplantation was not available for this patient. Plasma oxalate (Pox) was used as the primary outcome measure. RESULTS: Pox decreased from 104.3±8.4 prior to 70.0±15.0 µmol/L from Day 14 to Day 56 after LCT. A significant persistent Pox reduction (P<0.001) comparing mean levels prior to (103.8 µmol/L) and after Day 14 of LCT until LKTx (77.3 µmol/L) was seen, although a secondary increase and wider range of Pox was also observed. In parallel, the patient's clinical situation markedly improved and the girl received a cadaveric LKTx 12 months after LCT. However, biopsy specimens taken from the explanted liver did not show male donor cells by amelogenin polymerase chain reaction. CONCLUSIONS: With due caution, our pilot data indicate that LCT in infantile oxalosis warrants further investigation. Improvement of protocol and methodology is clearly needed in order to develop a procedure that could assist in the cure of PHI.

Massive macroglossia after palatoplasty: case report and review of the literature.

UNLABELLED: Cleft palates are among the most common birth defects. Serious complications in perioperative airway management after palatoplasty are rare and mostly described in children with preexisting compromise of airway due to craniofacial anomalies. A very uncommon but typical and frightening complication is postoperative extreme, very rapid emergence, and life-threatening macroglossia. While macroglossia usually has its peak within 24-48 h after palatoplasty and resolves spontaneously, we report a patient with massive lingual swelling with complete obstruction of the upper airway on the fifth postoperative day requiring tracheotomy. Swelling only resolved after removing the endotracheal tube after tracheotomy. Next to the description of our case, we discuss standard care procedure in perioperative management of patients with cleft palate to prevent this life-threatening complication after palatoplasty. CONCLUSION: Macroglossia can occur even 3-5 days after surgery and can be maintained by the pressure of the endotracheal tube to the tongue ground. Knowledge and avoidance of these risk factors are as important as early treatment of respiratory compromise.

Stereotactic brachytherapy with iodine-125 seeds for the treatment of inoperable low-grade gliomas in children: long-term outcome.

PURPOSE: Resection is generally considered the gold standard for treatment of low-grade (WHO grades I and II) gliomas (LGGs) in childhood. However, approximately 30% to 50% of these tumors are inoperable because of their localization in highly eloquent brain areas. A few reports have suggested stereotactic brachytherapy (SBT) with implantation of iodine-125 ((125)I) seeds as a safe and effective local treatment alternative. This single-center study provides a summary of the long-term outcome after SBT in one of the largest reported patient series. PATIENTS AND METHODS: All pediatric patients treated with SBT ((125)I seeds; cumulative therapeutic dose 50-65 Gy within 9 months) by our group for LGG with follow-up of more than 6 months were included. Clinical and radiologic outcome, time to progression, and overall survival were evaluated. Prognostic factors (age, sex, Karnofsky performance score, tumor volume, and histology) for survival and disease progression were investigated. RESULTS: In all, 147 of 160 pediatric patients treated with SBT (from 1982 through 2009) were analyzed in detail. Procedure-related mortality was zero, and the 30-day morbidity was transient and low (5.4%). Survival rates at 5 and 10 years were 93%, and 82%, respectively, with no significant difference between WHO grades I and II tumors (median follow-up, 67.1 ± 57.7 months). Twenty-one (14.8%) of 147 patients presented with tumor relapse. The remaining 126 patients revealed complete response in 24.6%, partial response in 31.0%, and stable disease in 29.6%. Neurologic status improved (57.8%) or remained stable (23.0%). None of the evaluated factors had significant impact on the study's end points except tumor volume more than 15 mL, which caused significantly higher rates of tumor recurrence (P < .05). CONCLUSION: We demonstrate that SBT represents a safe, minimally invasive, and highly effective local treatment option for pediatric patients with inoperable LGG WHO grades I and II.

Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics.

Joubert syndrome (JBTS) is characterized by a specific brain malformation with various additional pathologies. It results from mutations in any one of at least 10 different genes, including NPHP1, which encodes nephrocystin-1. JBTS has been linked to dysfunction of primary cilia, since the gene products known to be associated with the disorder localize to this evolutionarily ancient organelle. Here we report the identification of a disease locus, JBTS12, with mutations in the KIF7 gene, an ortholog of the Drosophila kinesin Costal2, in a consanguineous JBTS family and subsequently in other JBTS patients. Interestingly, KIF7 is a known regulator of Hedgehog signaling and a putative ciliary motor protein. We found that KIF7 co-precipitated with nephrocystin-1. Further, knockdown of KIF7 expression in cell lines caused defects in cilia formation and induced abnormal centrosomal duplication and fragmentation of the Golgi network. These cellular phenotypes likely resulted from abnormal tubulin acetylation and microtubular dynamics. Thus, we suggest that modified microtubule stability and growth direction caused by loss of KIF7 function may be an underlying disease mechanism contributing to JBTS.

Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta.

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.

A novel homozygous missense mutation in FGF23 causes Familial Tumoral Calcinosis associated with disseminated visceral calcification.

Hyperphosphatemic Familial Tumoral Calcinosis (HFTC; MIM211900) is a rare autosomal recessive disorder characterized by the progressive deposition of calcified masses in cutaneous and subcutaneous tissues, associated with elevated circulating levels of phosphate. The disease was initially found to result from mutations in GALNT3 encoding a glycosyltransferase. However, more recently, the S71G missense mutation in FGF23, encoding a potent phosphaturic protein, was identified in two families. In the present report, we describe a second mutation in FGF23 underlying a severe case displaying calcifications of cutaneous and numerous extracutaneous tissues. The mutation (M96T) was found to affect a highly conserved methionine residue at position 96 of the protein. These observations illustrate the extent of genetic and phenotypic heterogeneity in HFTC.