The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families.

PURPOSE: Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2, which is located in the Prader-Willi critical region 15q11-13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties, and autism spectrum disorder. The causality of the reported variants in the context of the patients' phenotypes was questioned, as MAGEL2 whole-gene deletions seem to cause little or no clinical phenotype. METHODS: Here we report a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families, including 1 family with 3 individuals found to be affected with a truncating variant of MAGEL2, 11 individuals who are clinically affected but were not tested molecularly, and a presymptomatic fetal sibling carrying the pathogenic MAGEL2 variant. RESULTS: All cases harbor truncating mutations of MAGEL2, and nucleotides c.1990-1996 arise as a mutational hotspot, with 10 individuals and 1 fetus harboring a c.1996dupC (p.Q666fs) mutation and 2 fetuses harboring a c.1996delC (p.Q666fs) mutation. The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to neurobehavioral disease and contractures of the small finger joints. CONCLUSION: This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2, refines the associated clinical phenotypes, and highlights implications for genetic counseling for affected families.Genet Med 19 1, 45-52.

Structured data entry for narrative data in a broad specialty: patient history and physical examination in pediatrics.

BACKGROUND: Whereas an electronic medical record (EMR) system can partly address the limitations, of paper-based documentation, such as fragmentation of patient data, physical paper records missing and poor legibility, structured data entry (SDE, i.e. data entry based on selection of predefined medical concepts) is essential for uniformity of data, easier reporting, decision support, quality assessment, and patient-oriented clinical research. The aim of this project was to explore whether a previously developed generic (i.e. content independent) SDE application to support the structured documentation of narrative data (called OpenSDE) can be used to model data obtained at history taking and physical examination of a broad specialty. METHODS: OpenSDE was customized for the broad domain of general pediatrics: medical concepts and its descriptors from history taking and physical examination were modeled into a tree structure. RESULTS: An EMR system allowing structured recording (OpenSDE) of pediatric narrative data was developed. Patient history is described by 20 main concepts and physical examination by 11. In total, the thesaurus consists of about 1800 items, used in 8648 nodes in the tree with a maximum depth of 9 levels. Patient history contained 6312 nodes, and physical examination 2336. User-defined entry forms can be composed according to individual needs, without affecting the underlying data representation. The content of the tree can be adjusted easily and sharing records among different disciplines is possible. Data that are relevant in more than one context can be accessed from multiple branches of the tree without duplication or ambiguity of data entry via "shortcuts". CONCLUSION: An expandable EMR system with structured data entry (OpenSDE) for pediatrics was developed, allowing structured documentation of patient history and physical examination. For further evaluation in other environments, the tree structure for general pediatrics is available at the Erasmus MC Web site (in Dutch, translation into English in progress) 1. The generic OpenSDE application is available at the OpenSDE Web site 2.

Application of a diagnostic decision rule in children with meningeal signs: a cost-minimization study.

OBJECTIVES: Recently, we developed a diagnostic rule for the diagnosis and treatment of children with meningeal signs. This rule may provide the physician with a rationale to decide on the use of diagnostic and treatment procedures in these children and to improve their care. In this study, we estimated cost savings of the rule compared with current practice. METHODS: Routine care data of 360 children visiting the emergency department of the Sophia Children's Hospital with meningeal signs between 1988 and 1998 were used. Costs of diagnostic tests and treatment were estimated by using financial accounts of an academic and a general pediatric hospital. The number of procedures actually performed and the resulting cost estimates (i.e. unit costs x volume) were compared with the estimated figures after application of the decision rule. RESULTS: The population of children with meningeal signs comprised 99 with bacterial meningitis (27%), 36 with another serious bacterial infection (10%), and 225 with a self-limiting disease (63%). Application of the rule would reduce lumbar punctures by 12% and hospitalizations for empirical treatment by 15% with the same diagnostic accuracy as current practice. Cost savings were estimated at Euro292 per patient (relative reduction 10%) and were mainly achieved in the treatment course (Euro259). CONCLUSIONS: A diagnostic decision rule for children with meningeal signs has the potential to improve the appropriate use of medical resources, to be cost-effective, and to ascertain the absence of bacterial meningitis earlier.

Cost-utility analysis of patient care in children with meningeal signs.

OBJECTIVES: We designed a model of diagnostic and therapeutic interventions applied in children with meningeal signs. Using this model, we determined in a cost-utility analysis the consequences for society of different diagnostic strategies in terms of quality-adjusted life-years (QALYs) and costs. METHODS: Data were used from 360 children (0.1-15 years) visiting the pediatric emergency department of the Sophia Children's Hospital Rotterdam, The Netherlands (1988-98) with meningeal signs. Model inputs included probabilities of meningitis and adverse outcome, QALYs for years lived with long-term sequelae, and costs of tests and treatments. Mean outcome measures were costs and effects of diagnostic and therapeutic interventions in children suspected of bacterial meningitis, key determinants of the model outcomes, and evaluation of alternative diagnostic strategies and two vaccination programs in an analysis. RESULTS: The population comprised 99 children with bacterial meningitis (adverse outcome in 10), 36 with serious other bacterial infections, and 225 with self-limiting diseases. Key determinants were the risk of bacterial meningitis or sequelae, costs of treatment, and long-term morbidity. Minimizing lumbar punctures and empirical treatments using a diagnostic decision rule, without missing a single case of meningitis, was a dominant strategy to actual practice. Vaccination strategies of Streptococcus pneumoniae and Neisseria meningitidis resulted in our model in incremental cost-utility ratios of 401,965 Euro dollar ([symbol: see text])/QALY and [symbol: see text]22,635/QALY, respectively. CONCLUSIONS: Costs of long-term morbidity of bacterial meningitis largely outweigh diagnostic and treatment costs. Modeling interventions in children at risk of bacterial meningitis should include long-term consequences in terms of costs and QALYs.