Exploring different stakeholders' perspectives on ward rounds in paediatric oncology: a qualitative study.

RATIONAL/AIMS AND OBJECTIVES: Ward rounds are a core routine for interprofessional communication and clinical care planning: Health care professionals and patients meet regularly and it encourages patients to actively participate. In paediatric oncology, the long treatment process, the serious diagnosis, and involvement of both patients and their parents in shared-decision-making require specific ward round skills. Despite its high value for patient-centred care, a universal definition of ward round is lacking. Little is known about attitudes and expectations of different participants towards a 'good' ward round. This study aims to capture experiences and expectations of different stakeholders to better understand ward round needs in paediatric oncology and serve as a basis to improve future ward rounds. METHOD: Semi-structured interviews were conducted with patients, parents, nurses and medical doctors of a paediatric oncology ward until theoretical saturation (13 interviews). A standardised qualitative analysis using the phenomenological framework defined by Colaizzi was used to identify important aspects in the interviews. RESULTS: Three major themes were identified in the interviews: [1] Structure and Organisation; [2] Communication; [3] Education. Further analysis revealed 23 categories and elucidated several opportunities and unmet needs recognized by stakeholders: Ward round functions in comforting families in stressful situations, and relationship building. Interviewees expressed their concerns about missing structures. Families pleaded for smaller ward round teams and layperson language. Health care professionals underscored the lack of ward round training. Paediatric patients stated that ward round scared them without proper explanation. All interviewees emphasized the need for professionalization of the ward round in the setting of paediatric oncology. CONCLUSION: This study gives important insights into ward round functions and organisational requirements. It addresses special challenges for ward round participants in paediatric oncology, such as consideration of the emotional aspect of cancer treatment or the limits of shared decision making. Furthermore, this study underscores the great significance of ward rounds in paediatric oncology, with an emphasis on communication and relationship-building. Although performed universally, ward rounds are poorly explored or evaluated. This structured analysis synthesizes important expectations of different WR stakeholders, revealing opportunities of improvement and stressing the need for guidelines, training, and preparation.

Development of a Social Network for People Without a Diagnosis (RarePairs): Evaluation Study.

BACKGROUND: Diagnostic delay in rare disease (RD) is common, occasionally lasting up to more than 20 years. In attempting to reduce it, diagnostic support tools have been studied extensively. However, social platforms have not yet been used for systematic diagnostic support. This paper illustrates the development and prototypic application of a social network using scientifically developed questions to match individuals without a diagnosis. OBJECTIVE: The study aimed to outline, create, and evaluate a prototype tool (a social network platform named RarePairs), helping patients with undiagnosed RDs to find individuals with similar symptoms. The prototype includes a matching algorithm, bringing together individuals with similar disease burden in the lead-up to diagnosis. METHODS: We divided our project into 4 phases. In phase 1, we used known data and findings in the literature to understand and specify the context of use. In phase 2, we specified the user requirements. In phase 3, we designed a prototype based on the results of phases 1 and 2, as well as incorporating a state-of-the-art questionnaire with 53 items for recognizing an RD. Lastly, we evaluated this prototype with a data set of 973 questionnaires from individuals suffering from different RDs using 24 distance calculating methods. RESULTS: Based on a step-by-step construction process, the digital patient platform prototype, RarePairs, was developed. In order to match individuals with similar experiences, it uses answer patterns generated by a specifically designed questionnaire (Q53). A total of 973 questionnaires answered by patients with RDs were used to construct and test an artificial intelligence (AI) algorithm like the k-nearest neighbor search. With this, we found matches for every single one of the 973 records. The cross-validation of those matches showed that the algorithm outperforms random matching significantly. Statistically, for every data set the algorithm found at least one other record (match) with the same diagnosis. CONCLUSIONS: Diagnostic delay is torturous for patients without a diagnosis. Shortening the delay is important for both doctors and patients. Diagnostic support using AI can be promoted differently. The prototype of the social media platform RarePairs might be a low-threshold patient platform, and proved suitable to match and connect different individuals with comparable symptoms. This exchange promoted through RarePairs might be used to speed up the diagnostic process. Further studies include its evaluation in a prospective setting and implementation of RarePairs as a mobile phone app.

Künstliche Intelligenz zur diagnostischen Unterstützung ausgewählter seltener lysosomaler Speichererkrankungen: Ergebnisse einer Pilotstudie.

BACKGROUND: Diagnosing a rare metabolic disease challenges physicians and affected individuals and their families. To support the diagnostic pathway, a diagnostic tool was developed using the experiences of the affected individuals gained in interviews. METHODS: 17 interviews with parents or individuals with a selected rare metabolic disease (Mucopolysaccharidosis (MPS), M. Fabry and M. Gaucher) were performed and qualitatively analysed using the standardized methods of Colaizzi. The results are reflected in diagnostic questionnaires. The questionnaires were distributed and answered by parents or individuals with an established diagnosis of MPS, M. Fabry or M. Gaucher and a control group. Four combined data mining classifiers were trained to detect suspicious answer patterns in the questionnaires. RESULTS: 56 questionnaires were used for training and cross-validation tests of the binary data mining system resulting in a sensitivity value of 91% for the diagnosis 'MPS'. Another 20 questionnaires which have not been used for the training process could be evaluated as a preliminary prospective test. Out of these 20 questionnaires the test delivered 18 correct diagnoses (90%). DISCUSSION AND CONCLUSIONS: Questionnaires for diagnostic support based on interviews with parents and affected individuals were developed and answer patterns were analysed with an ensemble of classifiers. Although preliminary, the results illustrate the potential of answer pattern recognition using data mining techniques. This approach might prove useful for diagnostic support in selected metabolic diseases.

SICKO. Development of a Multi-Disciplinary Training-Concept for Paediatric Oncology.

Background Treating children with cancer requires multiple different skills. For the healthcare personnel (HCP) in Germany the practice of ongoing training to improve professional skills is almost non-existent. Therefore, we developed a programme called 'SICKO' to support HCPs skills and attitudes by means of a multidisciplinary workshop. Methods Following a qualitative analysis, we then designed a modular (3 day) workshop. During day one (8 h) participants learn practical skills, the fundamentals of chemotherapy, and effective communication skills. Workshop day 2 (8 h) includes education regarding the complications of cancer therapy (e. g. tumour-lysis syndrome, delayed methotrexate excretion), and their management. Topics during day 3 (8 h) include 'breaking bad news', conflict management in the team, infusion-related complications and 'crew resource management' (CRM). Results 43 nurses and 33 physicians participated between 2013 and 2015. All participants highly recommend the workshop. Participants felt that knowledge increased significantly after workshops and were more confident regarding challenging communications. Discussion/Conclusions Although long-term effects have not yet been evaluated, 'SICKO' offers the opportunity for HCP to train and experience simulated day-to-day challenges in the field of paediatric oncology.

[On the fast track to diagnosis : Recommendations for patients without a diagnosis]. / Kurze Wege zur Diagnose : Eine Handlungsempfehlung für Patienten ohne Diagnose.

BACKGROUND: Patients, who have spent many years without a proper diagnosis present an extraordinary problem to health care providers and to the healthcare system as a whole. A long 'diagnostic journey' increases the risk of disease chronification, as well as the number of therapy attempts, which could lead to iatrogenic impairment. New resources and specialized health care departments are being developed to help and support this patient group. One example of such department is the Interdisciplinary Competence Unit for Patients without a Diagnosis at the center for rare diseases in Bonn (ZSEB), Germany. OBJECTIVE: To shed light on the current health care management of patients without a diagnosis and to present an established directive to optimize the care for this patient group, as practiced at the InterPoD. METHODS: Showcase of directives and advice for the health care management of long-term patients without a diagnosis. RESULTS: Sociodemographic and clinical characteristics based on the treated patient collective at the InterPoD along with their directives, from the years 2014 to 2016. DISCUSSION: The descriptive statistics and the increasing number of treated patients are a first indication of the usefulness of InterPoD-related processes.

Diagnostic support for selected neuromuscular diseases using answer-pattern recognition and data mining techniques: a proof of concept multicenter prospective trial.

BACKGROUND: Diagnosis of neuromuscular diseases in primary care is often challenging. Rare diseases such as Pompe disease are easily overlooked by the general practitioner. We therefore aimed to develop a diagnostic support tool using patient-oriented questions and combined data mining algorithms recognizing answer patterns in individuals with selected neuromuscular diseases. A multicenter prospective study for the proof of concept was conducted thereafter. METHODS: First, 16 interviews with patients were conducted focusing on their pre-diagnostic observations and experiences. From these interviews, we developed a questionnaire with 46 items. Then, patients with diagnosed neuromuscular diseases as well as patients without such a disease answered the questionnaire to establish a database for data mining. For proof of concept, initially only six diagnoses were chosen (myotonic dystrophy and myotonia (MdMy), Pompe disease (MP), amyotrophic lateral sclerosis (ALS), polyneuropathy (PNP), spinal muscular atrophy (SMA), other neuromuscular diseases, and no neuromuscular disease (NND). A prospective study was performed to validate the automated malleable system, which included six different classification methods combined in a fusion algorithm proposing a final diagnosis. Finally, new diagnoses were incorporated into the system. RESULTS: In total, questionnaires from 210 individuals were used to train the system. 89.5 % correct diagnoses were achieved during cross-validation. The sensitivity of the system was 93-97 % for individuals with MP, with MdMy and without neuromuscular diseases, but only 69 % in SMA and 81 % in ALS patients. In the prospective trial, 57/64 (89 %) diagnoses were predicted correctly by the computerized system. All questions, or rather all answers, increased the diagnostic accuracy of the system, with the best results reached by the fusion of different classifier methods. Receiver operating curve (ROC) and p-value analyses confirmed the results. CONCLUSION: A questionnaire-based diagnostic support tool using data mining methods exhibited good results in predicting selected neuromuscular diseases. Due to the variety of neuromuscular diseases, additional studies are required to measure beneficial effects in the clinical setting.

Supporting diagnostic decisions using hybrid and complementary data mining applications: a pilot study in the pediatric emergency department.

INTRODUCTION: This article demonstrates the capacity of a combination of different data mining (DM) methods to support diagnosis in pediatric emergency patients. By using a novel combination of these DM procedures, a computer-based diagnosis was created. METHODS: A support vector machine (SVM), artificial neural networks (ANNs), fuzzy logics, and a voting algorithm were simultaneously used to allocate a patient to one of 18 diagnoses (e.g., pneumonia, appendicitis). Anonymized data sets of patients who presented in the emergency department (ED) of a pediatric care clinic were chosen. For each patient, 26 identical clinical and laboratory parameters were used (e.g., blood count, C-reactive protein) to finally develop the program. RESULTS: The combination of four DM operations arrived at a correct diagnosis in 98% of the cases, retrospectively. A subgroup analysis showed that the highest diagnostic accuracy was for appendicitis (97% correct diagnoses) and idiopathic thrombocytopenic purpura or erythroblastopenia (100% correct diagnoses). During the prospective testing, 81% of the patients were correctly diagnosed by the system. DISCUSSION: The combination of these DM methods was suitable for proposing a diagnosis using both laboratory and clinical parameters. We conclude that an optimized combination of different but complementary DM methods might serve to assist medical decisions in the ED.

Paediatric airway management in mucopolysaccharidosis 1: a retrospective case review.

CONTEXT: Airway management in children suffering from mucopolysaccharidosis 1 (Hurler syndrome) remains challenging despite advances in both treatment and airway management techniques. OBJECTIVES: Forty-one anaesthetic charts following ten children over a 6-year period (2004-2010) were reviewed with emphasis on airway problems. RESULTS: All children had early stem cell transplantation at the age of 2 years or earlier. Mean (SD) age was 5 (4.3) years. Mask ventilation was difficult in five of 41 (12%) anaesthetics or in three of ten children. There were 29 intubations. Direct laryngoscopy was described as difficult (Cormack and Lehane ≥3) on 11 occasions in five of ten children. There were three of 26 (12%) failed intubations with direct laryngoscopy. These situations were resolved by a fibre-optic procedure, by laryngeal mask airway (LMA) insertion or by use of a videolaryngoscope. A laryngeal mask airway was used 11 times to avoid invasive airway management and once when direct laryngoscopy was impossible. CONCLUSION: The airway management of children with mucopolysaccharidosis 1 remains critical, despite advances in both treatment and airway management techniques. Problems did not seem to increase as children grew older. We assume that technical improvements such as standardised use of the laryngeal mask airway or attached tube channel videolaryngoscopes as well as a stem cell transplantation treatment of the disease helped the management of older children with mucopolysaccharidosis 1.

Predictors of growth patterns in children with mucopolysaccharidosis I after haematopoietic stem cell transplantation.

Mucopolysaccharidosis type I (MPS I) is an autosomal-recessive metabolic disorder caused by an enzyme deficiency of lysosomal alpha-l-iduronidase (IDUA). Haematopoietic stem cell transplantation (HSCT) is the therapeutic option of choice in MPS I patients younger than 2.5 years, which has a positive impact on neurocognitive development. However, impaired growth remains a problem. In this monocentric study, 14 patients with MPS I (mean age 1.72 years, range 0.81-3.08) were monitored according to a standardised follow-up program after successful allogeneic HSCT. A detailed anthropometric program was carried out to identify growth patterns and to determine predictors of growth in these children. All patients are alive and in outpatient care (mean follow-up 8.1 years, range 0.1-16.0). Progressively lower standard deviation scores (SDS) were observed for body length (mean SDS -1.61; -4.58 - 3.29), weight (-0.56; -3.19 - 2.95), sitting height (-3.28; -7.37 - 0.26), leg length (-1.64; -3.88 - 1.49) and head circumference (0.91; -2.52 - 6.09). Already at the age of 24 months, significant disproportions were detected being associated with increasing deterioration in growth for age. Younger age at HSCT, lower counts for haemoglobin and platelets, lower potassium, higher donor-derived chimerism, higher counts for leukocytes and recruitment of a matched unrelated donor (MUD) positively correlated with body length (p ≤ 0.05). In conclusion, this study characterised predictors and aspects of growth patterns in children with MPS I after HSCT, underlining that early HSCT of MUD is essential for slowing body disproportion.

Infants and Newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB Registry: A Unique and Challenging Population.

Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005-2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option.

Variable disease progression after successful stem cell transplantation: prospective follow-up investigations in eight patients with Hurler syndrome.

We report the results of a prospective, standardized follow-up programme of eight children (median age at SCT 1.2 yr) with mucopolysaccharidosis (MPS1H, M. Hurler) transplanted using a fludarabine-based SCT. SCT resulted in stable engraftment without transplant-related mortality. All patients are alive, engrafted and in ambulatory care. During follow-up (median five yr, 1.9-8 yr), six of eight showed developmental delay (two severe, two mild/no), all eight had spinal deformities and one received hip surgery for acetabular dysplasia. Hand surgery for carpal tunnel release and trigger digits was required in five of the patients. The cranio-cervical junction was narrowed in four patients, one child having already received surgery. CC was present in all patients prior to SCT. It remained unchanged in seven and regressed in one child. Severe cardiac dysfunction was present in two of the eight children before SCT. Cardiac pump function was normal in six patients and ameliorated in two, while valve abnormalities could be detected in six patients. Currently, transplantation seems no longer the major obstacle for MPS1H patients, but the variable musculoskeletal disease progression after successful SCT remains a challenge. Patients with Hurler syndrome need specialized follow-up care because of their manifold health problems. The standardized follow-up presented here is a step to optimize care for MPS children and their families after SCT.

Oxaliplatin, irinotecan, and gemcitabine: a novel combination in the therapy of progressed, relapsed, or refractory tumors in children.

Therapeutic options for unresectable neuroendocrine carcinomas and relapsed or refractory solid tumors are still limited in pediatric patients. We present a retrospective review of 12 children (3 to 16 y) in a case series treated with a novel combination of oxaliplatin, irinotecan, and gemcitabine (triple therapy). We defined its feasibility in a mainly outpatient setting and assessed its toxicity and effectiveness. Three patients with unresectable neuroendocrine carcinomas received triple therapy as first-line treatment; 9 children with relapsed or refractory solid tumors of different entities were assigned after failure of standard treatment protocols. The treatment schedule comprised oxaliplatin (85 mg/m²), irinotecan (175 mg/m²), and gemcitabine (1,000 mg/m²), the latter to be repeated on day 8. A median of 7 cycles was applied. Nine of 12 patients showed hematotoxicity 0-III degrees. Gastrointestinal toxicity I-II degrees were handled satisfactorily by supportive drugs. Tumor response was defined as partial response in 1 of 12 children, stable disease in 8 of 12 children, and progressive disease in 3 of 12 children with a median time of disease control of 7 months. We regard triple therapy as a well-tolerated outpatient treatment option offering children a high quality of life and showing considerable effectiveness in delaying tumor progress.

Trigger finger in children with hurler syndrome - distribution pattern and treatment options.

Introduction: Mucopolysaccharidosis is a rare and congenital autosomal recessive lysosomal storage disorder of glycosaminoglycans. An enzyme defect leads to cell, tissue and organ dysfunction. Carpal tunnel syndrome and trigger finger are the results of mucopolysaccharid deposition. Material and methods: We are treating 6 patients with mucopolysaccharide associated trigger fingers in an interdisciplinary setting with the department of pediatric hematology and oncology at Hannover Medical School, where each patient is examined inter alia for symptoms of trigger finger annually. Besides an interview of the parents about abnormalities with regard to hand function, pain and/or neurologic symptoms the children are examined by palpation and by assessment of the active and passive range of finger motion. In the case of finger locking due to an impaired excursion of the flexor tendons in the A2 and A3 pulley region, we performed a trap-door incision technique for A2 pulley widening and a simple release of the A3 pulley. Results: In 6 patients 43 fingers were affected. The average age was 10 years. Pulley thickening was palpated in 19 fingers of to the left hand and 24 fingers of the right hand. In 7 fingers the A1 pulley was affected, in 28 fingers the A2 pulley and in 25 fingers the A3 pulley. The A4 and A5 pulley were not affected in any case. Trigger symptoms were seen in 13 fingers. Five of the 6 children were given an operation indication. In these cases we performed carpal tunnel release, release of Loge de Guyon, and trigger finger release, either in combination or alone. In all cases the procedure led to pain relief and functional improvement. Conclusion: The treatment of trigger fingers in children with mucopolysaccharidosis as a rare disease is challenging with regard to diagnostics and indication. The main treatment goal is pain relief and improvement of hand function.

Clinical and genetic risk factors define two risk groups of extracranial malignant rhabdoid tumours (eMRT/RTK).

INTRODUCTION: Extracranial rhabdoid tumours are rare, highly aggressive malignancies primarily affecting young children. The EU-RHAB registry was initiated in 2009 to prospectively collect data of rhabdoid tumour patients treated according to the EU-RHAB therapeutic framework. METHODS: We evaluated 100 patients recruited within EU-RHAB (2009-2018). Tumours and matching blood samples were examined for SMARCB1 mutations by sequencing and cytogenetics. RESULTS: A total of 70 patients presented with extracranial, extrarenal tumours (eMRT) and 30 with renal rhabdoid tumours (RTK). Nine patients demonstrated synchronous tumours. Distant metastases at diagnosis (M+) were present in 35% (35/100), localised disease (M0) with (LN+) and without (LN-) loco-regional lymph node involvement in 65% (65/100). SMARCB1 germline mutations (GLM) were detected in 21% (17/81 evaluable) of patients. The 5-year overall survival (OS) and event-free survival (EFS) rates were 45.8 ± 5.4% and 35.2 ± 5.1%, respectively. On univariate analyses, age at diagnosis (≥12 months), M0-stage, absence of synchronous tumours, absence of a GLM, gross total resection (GTR), radiotherapy and achieving a CR were significantly associated with favourable outcomes. In an adjusted multivariate model presence of a GLM, M+ and lack of a GTR were the strongest significant negative predictors of outcome. CONCLUSIONS: We suggest to stratify patients with localised disease (M0), GTR+ and without proof of a GLM (5-year OS 72.2 ± 9.9%) as 'standard risk'. Patients presenting with one of the features M+ and/or GTR- and/or GLM+ belong to a high risk group (5-year, OS 32.5 ± 6.2%). These patients need novel therapeutic strategies such as combinations of targeted agents with conventional chemotherapy or novel experimental approaches ideally within international phase I/II trials.

Pain reduction in children during port-à-cath catheter puncture using local anaesthesia with EMLA™.

INTRODUCTION: Alleviating pain is of high importance for children undergoing chemotherapy. Eutectic mixture of lidocain-prilocain cream (EMLA) is assumed to require 60 min application time. MATERIALS AND METHODS: We prospectively compared the pain during port-à-cath punctures after 40 min compared to 60 min of application time. A prospective, unblinded, cross-over study was performed. The children received two punctures during their chemotherapy protocol. Patients in group 1 had the first puncture after 40 min EMLA application time. Their second puncture (approximately a week later) was done after 60 min. Patients in group 2 started after 40 min. Pain was scored using the visual analogue scale (VAS) and the Bieri scale. Patients, parents and a nurse scaled the pain after the intervention. Eighty-seven children between 2 and 18 years with different malignant diseases were included. RESULTS AND DISCUSSION: On the VAS pain scale, the mean pain was 2.3 (minimum 0, maximum 9.2) after 40 min and 1.9 (minimum 0, maximum 9.4) after 60 min according to the observations of the nurse and very similarly according to the parents' observations. The children expressed more pain after 40 min of EMLA application time (mean pain, 3.5) and a significant pain reduction after 60 min application time (mean pain 1.7). CONCLUSION: In this study children experienced less pain after 60 min application time, but pain reduction was already seen after 40 min. The child's perception of pain differed from observers' point of view and should therefore always be included in pain management.

Rapid development of a digital module during the Covid 19 pandemic in undergraduate medical education of pediatrics by teachers and students.

Objective: During the early Covid 19 pandemic, undergraduate medical teaching of pediatric medicine had to be switched to online teaching at the Hanover Medical School (MHH). The aim was to develop an online module together with students. Methodology: In a multi-stage process, a working group consisting of lecturers and students developed the concept and implemented it. Afterwards the online module was evaluated. Results: The conceptualization process and the implementation of the module together with students can be represented as a modified PDCA cycle (Plan-Do-Check-Act). We showed that including students in the development of an online module is helpful in times of limited resources e.g. such as personnel and time. Conclusion: The cooperation between students and lecturers is suitable for developing and implementing an online module in a short time. In the future, in addition to joint conceptualization phases, digital elements (e.g. preparatory webinars) for the module itself in attendance phases should be retained.

Hematopoietic stem cell transplantation in mucopolysaccharidosis type IIIA: A case description and comparison with a genotype-matched control group.

BACKGROUND: Mucopolysaccharidosis type IIIA (MPS IIIA, Sanfilippo A syndrome) is a chronic progressive neurodegenerative storage disorder caused by a deficiency of lysosomal sulfamidase. The clinical hallmarks are sleep disturbances, behavioral abnormalities and loss of cognitive, speech and motor abilities. Affected children show developmental slowing from the second year of life, dementia occurs by the age of 5 years followed by death in the second decade of life. Only a few studies concerning HSCT in MPS IIIA have been published and do not document a clear benefit of treatment. METHODS: The present study summarizes the clinical outcome of a girl with MPS IIIA who received HSCT at the age of 2.5 years. Her clinical course was compared with the natural history of six untreated MPS IIIA patients carrying the same mutations (p.R74C and p. R245H) in the SGSH-gene. RESULTS: Eight years after successful HSCT, the patient showed a global developmental delay. However, cognitive abilities continued to develop, albeit very slowly. There was no sign of regression. She could talk in short sentences, had good motor abilities and performed basic daily living activities by herself. She did not present with sleeping problems, but behavioral abnormalities were profound. In contrast, the six untreated patients with identical mutations in the SGSH-gene showed the typical progressive course of disease with early and continuous loss of abilities. CONCLUSIONS: The present data suggest a beneficial effect of HSCT performed at an early stage of MPS IIIA on cognitive skills, motor function and quality of life.

Common pre-diagnostic features in individuals with different rare diseases represent a key for diagnostic support with computerized pattern recognition?

BACKGROUND: Rare diseases (RD) result in a wide variety of clinical presentations, and this creates a significant diagnostic challenge for health care professionals. We hypothesized that there exist a set of consistent and shared phenomena among all individuals affected by (different) RD during the time before diagnosis is established. OBJECTIVE: We aimed to identify commonalities between different RD and developed a machine learning diagnostic support tool for RD. METHODS: 20 interviews with affected individuals with different RD, focusing on the time period before their diagnosis, were performed and qualitatively analyzed. Out of these pre-diagnostic experiences, we distilled key phenomena and created a questionnaire which was then distributed among individuals with the established diagnosis of i.) RD, ii.) other common non-rare diseases (NRO) iii.) common chronic diseases (CD), iv.), or psychosomatic/somatoform disorders (PSY). Finally, four combined single machine learning methods and a fusion algorithm were used to distinguish the different answer patterns of the questionnaires. RESULTS: The questionnaire contained 53 questions. A total sum of 1763 questionnaires (758 RD, 149 CD, 48 PSY, 200 NRO, 34 healthy individuals and 574 not evaluable questionnaires) were collected. Based on 3 independent data sets the 10-fold stratified cross-validation method for the answer-pattern recognition resulted in sensitivity values of 88.9% to detect the answer pattern of a RD, 86.6% for NRO, 87.7% for CD and 84.2% for PSY. CONCLUSION: Despite the great diversity in presentation and pathogenesis of each RD, patients with RD share surprisingly similar pre-diagnosis experiences. Our questionnaire and data-mining based approach successfully detected unique patterns in groups of individuals affected by a broad range of different rare diseases. Therefore, these results indicate distinct patterns that may be used for diagnostic support in RD.

Lethal graft-versus-host disease in congenital neutropenia caused by p14 deficiency after allogeneic bone marrow transplantation from an HLA-identical sibling.

The molecular heterogeneity of severe congenital neutropenia (SCN) is increasingly recognized and may influence the risk-benefit assessment of therapeutic strategies. We report on a patient with p14 deficiency who succumbed to severe grade IV graft-versus-host disease (GvHD) after a human leukocyte antigen-identical bone marrow transplantion (BMT) from a sibling donor. Before BMT, in vitro generated p14-deficient dendritic cells showed a markedly elevated tumor necrosis factor (TNF-) alpha production upon toll-like receptor stimulation. We hypothesize that p14 deficiency predisposes to GvHD through increased TNF-alpha production. Adequate genetic testing is needed to prospectively assess potential risk factors for GvHD in defined SCN subgroups.