Niels Ove Illum

A Dominant Mutation in the Gene Encoding the Erythroid Transcription Factor KLF1 Causes a Congenital Dyserythropoietic Anemia

The congenital dyserythropoietic anemias (CDAs) are inherited red blood cell disorders whose hallmarks are ineffective erythropoiesis, hemolysis, and morphological abnormalities of erythroblasts in bone marrow. We have identified a missense mutation in KLF1 of patients with a hitherto unclassified CDA. KLF1 is an erythroid transcription factor, and extensive studies in mouse models have shown that it plays a critical role in the expression of globin genes, but also in the expression of a wide spectrum of genes potentially essential for erythropoiesis. The unique features of this CDA confirm the key role of KLF1 during human erythroid differentiation. Furthermore, we show that the mutation has a dominant-negative effect on KLF1 transcriptional activity and unexpectedly abolishes the expression of the water channel AQP1 and the adhesion molecule CD44. Thus, the study of this disease-causing mutation in KLF1 provides further insights into the roles of this transcription factor during erythropoiesis in humans.

Spinal cord injury at birth: a hidden causative factor

A case of perinatally acquired spinal cord injury (SCI) is presented. The foetus was vigorous until birth, the breech presented and delivery was performed by a non‐traumatic Caesarean section. The infant displayed symptoms of severe SCI but diagnosis was delayed due to severe co‐morbidity. Diagnostic considerations are briefly reviewed. Ventilatory support was withdrawn at the age of 20 days when the infant had still not exhibited any respiratory effort or spontaneous movements. Autopsy revealed a serious congenital malalignment of the upper cervical vertebrae and at the histological examination extensive reactive changes were observed in the same area. To our knowledge such findings have not been published previously.

The Nordic Five to Fifteen questionnaire could provide the basis for a common neurological disability variable

Assessing disabilities in children is essential and Danish parents provide increasingly important feedback on how their childs disability affects daily living. The Nordic Five to Fifteen (FTF) parent questionnaire is widely used in Nordic countries to detect atypical or delayed development in children. Our study evaluated its internal validity and whether it could be used to generate a common disability variable across childhood neurological disorders and severities.

Eponymous Jacobsen syndrome: mapping the breakpoints of the original family suggests an association between the distal 1.1 Mb of chromosome 21 and osteoporosis in Down syndrome.

Z. Tumer,* A.M. Henriksen, I. Bache, K. Brixen, V. Kalscheuer, N. Illum, K. Rasmussen, L.A. Larsen, and N. Tommerup Department of Medical Biochemistry and Genetics, Wilhelm Johannsen Centre for Functional Genome Research, The Panum Institute, University of Copenhagen, Copenhagen, Denmark Department of Endocrinology, Odense University Hospital, Odense, Denmark Max-Planck Institute of Molecular Genetics, Berlin, Germany Department of Pediatrics H, Odense University Hospital, Odense, Denmark Department of Clinical Biochemistry and Genetics, Odense University Hospital, Odense, Denmark

Creating a Disability Variable for Children with Disability Using the WHO ICF - CY Classification System

Aims: To create a single disability variable in 332 children with different disability severities, ICD-10 diagnoses, and ages by employing the WHO ICF-CY body functions coding system. Study Design: Open field pilot research study. Place and Duration of Study: H. C. Andersen Children’s Hospital and Centre for Clinical Epidemiology, Odense University Hospital, Odense Denmark, between October 2010 and November 2011. Methodology: We included 332 children (144 boys and 188 girls; age range 1.0–15.9 years) with spina bifida, spinal muscular atrophy, muscular disorders, cerebral palsy, visual impairment, hearing impairment, mental disability, and disabilities following treatment for a brain tumour. A set of 47 body function codes (b codes) representing a broad spectrum of functions in daily living and with five qualifiers each was scored during interviews with parents. Psychometric and Rasch data analyses were performed. Original Research Article Illum and Gradel; BJAST, 11(1): 1-19, 2015; Article no.BJAST.19635 2 Results: Mean code score for each child was 32.17 (range 0–159). The corrected code-total correlation was high (0.70). Inter-code correlation was mean 0.50 (range 0.01–0.97), and Cronbach s alpha 0.98. Following Rasch analysis and due to disordering of Andrich thresholds (τs) and infit and outfit mean square values >1.5, the number of codes was reduced from 47 to 33. Retained codes all had ordered τs and mean square and corresponding Z-standardised values within the recommended range of 0.5–1.5. The t-statistic for differential item functioning across codes and diagnosis group, age, and gender was between 2.0 and 3.0. Graphical data for disability variable, the child-code map, paralleled clinical expectations across the total population of children. Conclusion: WHO ICF-CY b codes can provide a coherent measure of the severity of disability in children across various diagnoses, age, and gender and add important information to WHO ICD-10 diagnosis codes when employed in daily clinical practice.

Parents’ Assessments of Disability in Their Children Using World Health Organization International Classification of Functioning, Disability and Health, Child and Youth Version Joined Body Functions and Activity Codes Related to Everyday Life

Aim: To help parents assess disability in their own children using World Health Organization (WHO) International Classification of Functioning, Disability and Health, Child and Youth Version (ICF-CY) code qualifier scoring and to assess the validity and reliability of the data sets obtained. Method: Parents of 162 children with spina bifida, spinal muscular atrophy, muscular disorders, cerebral palsy, visual impairment, hearing impairment, mental disability, or disability following brain tumours performed scoring for 26 body functions qualifiers (b codes) and activities and participation qualifiers (d codes). Scoring was repeated after 6 months. Psychometric and Rasch data analysis was undertaken. Results: The initial and repeated data had Cronbach α of 0.96 and 0.97, respectively. Inter-code correlation was 0.54 (range: 0.23-0.91) and 0.76 (range: 0.20-0.92). The corrected code-total correlations were 0.72 (range: 0.49-0.83) and 0.75 (range: 0.50-0.87). When repeated, the ICF-CY code qualifier scoring showed a correlation R of 0.90. Rasch analysis of the selected ICF-CY code data demonstrated a mean measure of 0.00 and 0.00, respectively. Code qualifier infit mean square (MNSQ) had a mean of 1.01 and 1.00. The mean corresponding outfit MNSQ was 1.05 and 1.01. The ICF-CY code τ thresholds and category measures were continuous when assessed and reassessed by parents. Participating children had a mean of 56 codes scores (range: 26-130) before and a mean of 55.9 scores (range: 25-125) after repeat. Corresponding measures were −1.10 (range: −5.31 to 5.25) and −1.11 (range: −5.42 to 5.36), respectively. Based on measures obtained at the 2 occasions, the correlation coefficient R was 0.84. The child code map showed coherence of ICF-CY codes at each level. There was continuity in covering the range across disabilities. And, first and foremost, the distribution of codes reflexed a true continuity in disability with codes for motor functions activated first, then codes for cognitive functions, and, finally, codes for more complex functions. Conclusions: Parents can assess their own children in a valid and reliable way, and if the WHO ICF-CY second-level code data set is functioning in a clinically sound way, it can be employed as a tool for identifying the severity of disabilities and for monitoring changes in those disabilities over time. The ICF-CY codes selected in this study might be one cornerstone in forming a national or even international generic set of ICF-CY codes for the benefit of children with disabilities, their parents, and caregivers and for the whole community supporting with children with disabilities on a daily and perpetual basis.

Assessing Children With Disabilities Using WHO International Classification of Functioning, Disability and Health Child and Youth Version Activities and Participation D Codes

Aim: Evaluation of the International Classification of Functioning, Disability and Health child and youth version (ICF-CY) activities and participation d code functions in clinical practice with children across diagnoses, disabilities, ages, and genders. Methods: A set of 57 codes were selected and worded to describe children’s support needs in everyday life. Parents of children aged 1 to 15 years participated in interviews to discuss and rate their child’s disability. Results: Of 367 invited parents, 332 (90.5%) participated. The mean age of their children with disability was 9.4 years. The mean code scores were 50.67, the corrected code–total correlations were .76, intercode correlations had the mean of 0.61, and Cronbach’s α was .98. As a result of Rasch analysis, graphical data for disability measures paralleled clinical expectations across the total population of 332 children. Conclusion: The World Health Organization International Classification of Functioning, Disability and Health child and youth version d code data can provide a coherent measure of severity of disability in children across various diagnoses, ages, and genders.

Recurrent nodular haemangiomas in Klippel-Tréaunay syndrome

A one‐year‐old child had hypertrophy of the left leg and an unusual constellation of a naevus flammeus and superficial enlarged veins of the trunk together with successive appearance and involution since birth of numerous nodular elements located in the naevus and in the surrounding normal skin. Microscopic examination of these elements showed haemangiomas with capillaries, cavernous channels and lymphangiomatous components. The benign nature of transient nodular elements located to the trunk and the lack of associated visceral vascular malformations in the Klippel‐Trénaunay syndrome are documented.

Is MED13L-related intellectual disability a recognizable syndrome?

INTRODUCTION MED13L-related intellectual disability is characterized by moderate intellectual disability (ID), speech impairment, and dysmorphic facial features. We present 8 patients with MED13L-related intellectual disability and review the literature for phenotypical and genetic aspects of previously described patients. MATERIALS AND METHODS In the search for genetic aberrations in individuals with ID, two of the patients were identified by chromosomal microarray analysis, and five by exome sequencing. One of the individuals, suspected of MED13L-related intellectual disability, based on clinical features, was identified by Sanger sequencing. RESULTS All 8 individuals had de novo MED13L aberrations, including two intragenic microdeletions, two frameshift, three nonsense variants, and one missense variant. Phenotypically, they all had intellectual disability, speech and motor delay, and features of the mouth (open mouth appearance, macroglossia, and/or macrostomia). Two individuals were diagnosed with autism, and one had autistic features. One had complex congenital heart defect, and one had persistent foramen ovale. The literature was reviewed with respect to clinical and dysmorphic features, and genetic aberrations. CONCLUSIONS Even if most clinical features of MED13L-related intellectual disability are rather non-specific, the syndrome may be suspected in some individuals based on the association of developmental delay, speech impairment, bulbous nasal tip, and macroglossia, macrostomia, or open mouth appearance.

Parents' Expressions of Concerns and Hopes for the Future and Their Concomitant Assessments of Disability in Their Children

Aim: To assess parents’ ability to express their concerns and hopes for the future in their children with disability and assess their children’s disability as well as to analyse these data for consistency. Method: Parents of 162 children with spina bifida, spinal muscular atrophy, muscular disorders, cerebral palsy, visual impairment, hearing impairment, mental disability, or disability following brain tumours were asked to freely express their concerns and hopes for the future and to assess disability in their own children by employing a set of 26 International Classification of Functioning, Disability and Health, Children and Youth Version (ICF-CY) body function (b) codes and activity and participation (d) codes. A grounded theory approach was employed to systematize parents’ expressions of concerns and hopes; then, parents scored qualifiers on a 5-step qualitative Likert scale. Parents assessed their children’s disability in the same way using the ICF-CY 5-step qualifier scale. Results: Altogether, 119 parents freely expressed their concerns and hopes, and 101 of them also assessed their children’s disability using the 26 ICF-CY codes. A total of 475 expressions of concern and hopes (issues) were expressed and categorized into 34 areas of concern and hopes (subsections). The most frequently mentioned issues were education; understanding, goodwill, and communication between parents; and community support. Qualitative data on both 5-step qualifier scales showed good reliability. Rasch analysis maps on concerns and hopes for children as well as on the ICF-CY assessment demonstrated good alignment and a clinically relevant progression from the least to the most disabled children. Conclusion: Parents can express valid and reliable data on their concerns and hopes for the future and can reliably assess disability in their own children.