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Background Hypophosphatasia (HPP) is a rare, inherited metabolic disorder caused by loss-of-function mutations in the ALPL gene that encodes the tissue-nonspecific alkaline phosphatase TNAP (ORPHA 436). Its clinical presentation is highly heterogeneous with a remarkably wide-ranging severity. HPP affects patients of all ages. In children HPP-related musculoskeletal symptoms may mimic rheumatologic conditions and diagnosis is often difficult and delayed. To improve the understanding of HPP in children and in order to shorten the diagnostic time span in the future we studied the natural history of the disease in our large cohort of pediatric patients. This single centre retrospective chart review included longitudinal data from 50 patients with HPP diagnosed and followed at the University Children’s Hospital Wuerzburg, Germany over the last 25 years. Results The cohort comprises 4 (8%) perinatal, 17 (34%) infantile and 29 (58%) childhood onset HPP patients. Two patients were deceased at the time of data collection. Diagnosis was based on available characteristic clinical symptoms (in 88%), low alkaline phosphatase (AP) activity (in 96%), accumulating substrates of AP (in 58%) and X-ray findings (in 48%). Genetic analysis was performed in 48 patients (31 compound heterozygous, 15 heterozygous, 2 homozygous mutations per patient), allowing investigations on genotype-phenotype correlations. Based on anamnestic data, median age at first clinical symptoms was 3.5 months (min. 0, max. 107), while median time to diagnosis was 13 months (min. 0, max. 103). Common symptoms included: impairment of motor skills (78%), impairment of mineralization (72%), premature loss of teeth (64%), musculoskeletal pain and craniosynostosis (each 64%) and failure to thrive (62%). Up to now 20 patients started medical treatment with Asfotase alfa. Conclusions Reported findings support the clinical perception of HPP being a chronic multi-systemic disease with often delayed diagnosis. Our natural history information provides detailed insights into the prevalence of different symptoms, which can help to improve and shorten diagnostics and thereby lead to an optimised medical care, especially with promising therapeutic options such as enzyme-replacement-therapy with Asfotase alfa in mind.

Positional plagiocephaly (PP) is the most common skull deformity in infants. Different classification systems exist for graduating the degree of PP, but all of these systems are based on two-dimensional (2D) parameters. This limitation leads to several problems stemming from the fact that 2D parameters are used to classify the three-dimensional (3D) shape of the head. We therefore evaluate existing measurement parameters and validate a newly developed 3D parameter for quantifying PP. Additionally, we present a new classification of PP based on a 3D parameter. 210 patients with PP and 50 patients without PP were included in this study. Existing parameters (2D and 3D) and newly developed volume parameters based on a 3D stereophotogrammetry scan were validated using ROC curves. Additionally, thresholds for the new 3D parameter of a 3D asymmetry index were assessed. The volume parameter 3D asymmetry index quantifies PP equally as well as the gold standard of 30° diagonal difference . Moreover, a 3D asymmetry index allows for a 3D-based classification of PP. The 3D asymmetry index can be used to define the degree of PP. It is easily applicable in stereophotogrammetric datasets and allows for comparability both intra- and inter-individually as well as for scientific analysis.

Pre-mRNA splicing is a fundamental step in protein synthesis within a cell. Malfunctions during this process can lead to dysfunctional proteins and thus, to a variety of different human diseases. Mis-splicing can be caused by genetic variants influencing many different molecular processes, e.g. splice donor and splice acceptor site variants. Today, the consequences of these variants can be calculated via different in-silico programs. Due to the complexity of the splicing process, however, these predictions are not always correct and should not be used as stand-alone criteria for the classification of potentially disease-causing variants. Therefore, in case RNA from an appropriate tissue is not available additional in-vitro studies, such as a minigene splice assay, which allows functional analyses of potentially disease-causing variants, are necessary to demonstrate an effect on splicing. One example of a human developmental disorder occasionally caused by mis-splicing of transcripts is craniosynostosis. This congenital disorder is defined by the premature fusion of one or multiple cranial sutures in the neurocranium. To date, numerous mutation types in more than 50 genes which are involved in a broad range of different cellular functions and pathways have been associated with craniosynostosis. For instance, the TCF12 gene encoding the bHLH (basic helix-loop-helix) protein TCF12 (transcription factor 12) is linked to Craniosynostosis 3 (OMIM: 615314) which exhibits a Saethre-Chotzen (OMIM:101400) like phenotype. In this study, we report a pipeline for functional validation of potential splice site altering variants. First, we describe the identification of two novel genetic variants and revalidation of one previously described genetic variant in patients with craniosynostosis. According to in-silico predictions, the splicing of the corresponding transcripts is altered, and the variants are potentially disease causing. We subsequently classify the consequences of alterations in TCF12 experimentally. The suspected aberrant splicing was investigated via an in-vitro minigene splice assay. In two out of three variants, the in-silico prediction and in-vitro experiments were consistent. In all variants a significantly reduced transcriptional activity was demonstrated. In summary, the combination of in-silico prediction and functional assays allowed us to classify the variants as likely pathogenic without the need for additional patient material.

Objectives The present investigation aimed to evaluate the subjective perception of deformational cranial asymmetries by different observer groups and to compare these subjective perceptions with objective parameters. Materials and methods The 3D datasets of ten infants with different severities of deformational plagiocephaly (DP) were presented to 203 observers, who had been subdivided into five different groups (specialists, pediatricians, medical doctors (not pediatricians), parents of infants with DP, and laypersons). The observers rated their subjective perception of the infants’ cranial asymmetries using a 4-point Likert-type scale. The ratings from the observer groups were compared with one another using a multilevel modelling linear regression analysis and were correlated with four commonly used parameters to objectively quantify the cranial asymmetries. Results No significant differences were found between the ratings of the specialists and those of the parents of infants with DP, but both groups provided significantly more asymmetric ratings than did pediatricians, medical doctors, or laypersons. Moreover, the subjective perception of cranial asymmetries correlated significantly with commonly used parameters for objectively quantifying cranial asymmetries. Conclusions Our results demonstrate that different observer groups perceive the severity of cranial asymmetries differently. Pediatricians’ more moderate perception of cranial asymmetries may reduce the likelihood of parents to seek therapeutic interventions for their infants. Moreover, we identified some objective symmetry-related parameters that correlated strongly with the observers’ subjective perceptions. Clinical relevance Knowledge about these findings is important for clinicians when educating parents of infants with DP about the deformity.

ObjectiveAlthough prematurity is a risk factor for developing deformational plagiocephaly (DP), to our knowledge, there are no studies that have analyzed the impact of a premature birth on the duration of head orthosis therapy and the extent of the reduction in asymmetry during treatment.Materials and MethodsWe examined 239 patients with DP who were undergoing head orthosis therapy. Depending on the gestational age, they were assigned to either a premature (gestational age of < 37 weeks) or a full-term (gestational age of ≥ 37 weeks) group. Head shape was analyzed using 3D-stereophotogrammetry at the start and end of treatment. We performed multiple linear regression analyses to evaluate the impact of prematurity on the duration of therapy and the extent of the reduction in asymmetry, taking age and the initial asymmetry of an infant’s head into account.ResultsHead orthosis therapy led to a significant reduction in asymmetry in both groups. Using multiple linear regression analyses, we demonstrated that age at the start of treatment, the initial asymmetry and prematurity, significantly influenced the duration of therapy. Patients who were born at an earlier gestational age experienced a shorter treatment length. However, prematurity did not affect the extent of the reduction in cranial asymmetry that was achieved.ConclusionsAlong with age at the start of treatment and the initial asymmetry, prematurity is significantly correlated with the duration of head orthosis therapy, but not with the extent of the reduction in asymmetry achieved.Clinical RelevanceKnowledge of these findings is important for clinicians when planning treatment and discussing the effectiveness of head orthosis therapy with the parents of premature infants with DP.

Background: Intracranial choroid plexus tumors (CPT) are rare and primarily affect young children. Leptomeningeal dissemination (LMD) has been reported not only in high-grade choroid plexus carcinoma (CPC) but also in lower histological grades; however, a systematic evaluation of CPT-specific imaging characteristics remains lacking. Methods: We analyzed the imaging characteristics of LMD in a single-center pediatric cohort of 22 CPT patients (thirteen choroid plexus papilloma (CPP), six atypical choroid plexus papilloma (aCPP), three CPC), comparing LMD features with those of the primary tumor. Additionally, we examined the correlation between resection status and LMD development during follow-up. Results: At diagnosis, we observed true LMD in three (two CPCs, one CPP) and pseudo-LMD in one case (CPP). During follow-up, two CPP patients developed cystic LMD, and one aCPP patient developed a solid metastasis. LMD had characteristics of the primary tumor in 3/4 cases. Incomplete resection was associated with a higher risk of LMD (p = 0.025). Conclusions: LMD can occur in both high- and lower-grade CPT, presenting at diagnosis as well as in relapsed lower-grade cases. Notable MR-imaging features include pseudo-LMD at diagnosis and cystic LMD in relapsed CPP cases. Incomplete tumor resection may increase the risk of LMD, although further validation is needed.

Background Medulloblastoma is the most common malignant brain tumor in children and can be divided in different molecular subgroups. Patients whose tumor is classified as a Group 3 tumor have a dismal prognosis. However only very few tumor models are available for this subgroup. Methods We established a robust orthotopic xenograft model with a cell line derived from the malignant pleural effusions of a child suffering from a Group 3 medulloblastoma. Results Besides classical characteristics of this tumor subgroup, the cells display cancer stem cell characteristics including neurosphere formation, multilineage differentiation, CD133/CD15 expression, high ALDH-activity and high tumorigenicity in immunocompromised mice with xenografts exactly recapitulating the original tumor architecture. Conclusions This model using unmanipulated, human medulloblastoma cells will enable translational research, specifically focused on Group 3 medulloblastoma.

Purpose In craniofacial surgery, the stable fixation of transposed bone segments is crucial in order to ensure good long-term results. The use of absorbable material in fixation avoids the need for a second surgery, which would otherwise be required to remove osteosynthesis material. The authors of the present manuscript have already demonstrated that absorbable sutures ensure the stable fixation of bone segments in patients up to 24 months of age. However, it has thus far remained unclear whether stable fixation is possible in older patients by using only absorbable sutures due to the slower bone remodelling and prolonged healing time in this cohort. Method For the present study, osteosynthesis was performed in 50 patients ranging from 25.7 to 192.1 months of age (mean, 61.4 ± 21.7 months) using solely absorbable sutures (PDS II ® , Ethicon, Germany). Post-operative stability and possible restrictions—such as foreign body reactions—were evaluated within clinical and radiological routine follow-ups. Results All children demonstrated clinically and radiologically stable osteosynthesis both directly post-operatively and in follow-ups. No significant foreign body reaction could be seen. Conclusion The present study demonstrates—for the first time—that absorbable sutures with a longer absorption period are also very well suited for the fixation of bone segments in patients over 24 months of age. The sole use of absorbable sutures in children over 24 months of age is a safe procedure with nearly no foreign body reactions. The procedure enables stable and highly cost-effective osteosynthesis without altering the osteotomy design.

Objective We defined parameters that could differentiate between positional and synostotic plagiocephaly and defined a diagnostic chart for decision making. Design Prospective study. Setting We examined 411 children with non-syndromic skull abnormalities between January 2011 and December 2012. Participants A total of 8 infants under 1 year of age with proven unilateral non-syndromic lambdoid synostosis (LS) and 261 children with positional deformity were examined to outline the specific clinical features of both diagnoses. After clinical examination, an ultrasound revealed either a closed suture suggestive of LS or a patent lambdoid suture suggestive of positional deformity. For patients with synostosis, plain radiographs, MR imaging and follow-up examinations were performed. In cases of open sutures, only follow-ups were completed. Main outcome measure Clinical, imaging, genesis and treatment differences between positional plagiocephaly and LS. Results In all 8 cases of unilateral LS and 258 cases of positional plagiocephaly, the diagnosis was established by clinical examination alone. In three cases of positional plagiocephaly, diagnosis was determined after an additional ultrasonography. MR imaging revealed a unilateral tonsillar herniation in five of the eight children with LS and hydrocephalus in one child. Conclusions We have suggested a list of clinical features that specify the underlying cause of posterior plagiocephaly. An additional ultrasound scanning confirmed the diagnosis without any risks of ionising radiation or sedation as in a CT scan.