• Astroglial-Mediated Remodeling of the Interhemispheric Midline Is Required for the Formation of the Corpus Callosum.

      Gobius, Ilan; Morcom, Laura; Suárez, Rodrigo; Bunt, Jens; Bukshpun, Polina; Reardon, William; Dobyns, William B; Rubenstein, John L R; Barkovich, A James; Sherr, Elliott H; et al. (CellPress, 2016)
      The corpus callosum is the major axon tract that connects and integrates neural activity between the two cerebral hemispheres. Although ∼1:4,000 children are born with developmental absence of the corpus callosum, the primary etiology of this condition remains unknown. Here, we demonstrate that midline crossing of callosal axons is dependent upon the prior remodeling and degradation of the intervening interhemispheric fissure. This remodeling event is initiated by astroglia on either side of the interhemispheric fissure, which intercalate with one another and degrade the intervening leptomeninges. Callosal axons then preferentially extend over these specialized astroglial cells to cross the midline. A key regulatory step in interhemispheric remodeling is the differentiation of these astroglia from radial glia, which is initiated by Fgf8 signaling to downstream Nfi transcription factors. Crucially, our findings from human neuroimaging studies reveal that developmental defects in interhemispheric remodeling are likely to be a primary etiology underlying human callosal agenesis.
    • NSD1 mutations generate a genome-wide DNA methylation signature.

      Choufani, S; Cytrynbaum, C; Chung, B H Y; Turinsky, A L; Grafodatskaya, D; Chen, Y A; Cohen, A S A; Dupuis, L; Butcher, D T; Siu, M T; et al. (Nature Publishing Group, 2015-12-22)
      Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1. As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1(+/-)-specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1(+/-) signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing.
    • A paediatric hernia with a twist: the presentation, imaging findings and management of a strangulated ovarian hernia

      Hughes, P; Abdelhafeez, A; Byrne, AT; Rea, D; JGillick, J (Irish Medical Journal, 2015-10)
      Indirect inguinal hernias are the most commonly encountered congenital abnormality in infants. 1,2 They may be complicated by herniation of abdominal or pelvic viscus. In girls, a herniated ovary is a relatively common finding, however torsion of the ovary is infrequent. A tender irreducible inguinal hernia in an infant girl should raise the possibility of a strangulated herniated ovary as it requires urgent surgical attention. When in doubt, ultrasound with colour Doppler easily confirms the diagnosis. Here we present the case of an ovarian inguinal hernia which had undergone torsion and review the presentation, imaging findings and management.
    • Further delineation of the KAT6B molecular and phenotypic spectrum.

      Gannon, Tamsin; Perveen, Rahat; Schlecht, Hélene; Ramsden, Simon; Anderson, Beverley; Kerr, Bronwyn; Day, Ruth; Banka, Siddharth; Suri, Mohnish; Berland, Siren; et al. (Nature Publishing Group, 2015-09)
      KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.
    • Influence of curve magnitude and other variables on operative time, blood loss and transfusion requirements in adolescent idiopathic scoliosis.

      Nugent, M; Tarrant, R C; Queally, J M; Sheeran, P; Moore, D P; Kiely, P J; Our Lady's Children's Hospital Crumlin; National Children's Research Centre Dublin 12 (2015-05-03)
      Posterior spinal instrumentation and fusion for correction of adolescent idiopathic scoliosis (AIS) typically requires lengthy operating time and may be associated with significant blood loss and subsequent transfusion. This study aimed to identify factors predictive of duration of surgery, intraoperative blood loss and transfusion requirements in an Irish AIS cohort.
    • The Prevalence of Cardiovascular Risk Factors in Obese Children

      Carolan, E; Hogan, A; O’Connell, J; Fallon, M; Byrne, D; O’Shea, D; Cody, D (Irish Medical Journal, 2015-05)
      Childhood Obesity poses a public health problem in Ireland. Complications associated include metabolic disease and cardiovascular disease risk. Our aim was to determine the prevalence of cardiovascular risk factors in a cohort of obese Irish children. Assessments were performed on obese children attending weight management clinic. Pedometers and self report physical activity questionnaires were administered to each participant to determine physical activity levels. Fifty-nine children (21 prepubertal and 38 pubertal/post-pubertal) were metabolically profiled. Mean–SD of z scores for BMI, Waist Circumference and Body Fat % were +3.29–0.48, +3.98–0.73 and +2.75–0.50 respectively. 43% (n=9) prepubertal and 68% (n=26) pubertal/postpubertal children had at least one other cardiovascular risk factor in addition to obesity. Increased moderateâ vigorous physical activity levels correlated with reduced incidence of cardiovascular risk factors. There is a significant prevalence of cardiovascular risk factors among obese pre-pubertal children and pubertal/post-pubertal adolescents attending an Irish obesity clinic.
    • Myocardial ischaemia following cocaine and adrenaline exposure in a child during an ophthalmological procedure.

      McGovern, E; Moylett, E; McMahon, C J (Irish Medical Journal, 2015-03)
      We report a 23-month old girl who presented with bilateral epiphora who underwent bilateral lacrimal probing and syringing, during which a cocaine adrenaline solution was used. Two hours after the procedure she developed acute pulmonary oedema secondary to myocardial ischaemia. The patient was treated with intravenous glyceryltrinitrate and milrinone infusions; cardiac enzymes and left ventricular function normalised over the subsequent 72 hours. Topical administration of cocaine and adrenaline solution may have dangerous systemic cardiac effects and should always be used judiciously.
    • Diagnosis and treatment of sleep related breathing disorders in children: 2007 to 2011.

      Walsh, A; Phelan, F; Phelan, M; Ryan, M; Healy, F; Slattery, D M; Elnazir, B; Greally, P; Linnane, B; Ní Chróinín, M; et al. (Irish Medical Journal, 2015-03)
      Sleep related breathing disorders (SRBD) have historically been under-recognised and under-treated. Obstructive sleep apnoea (OSA) affects approximately 3% of children. In line with the increased recognition of SRBD there has been an increase in demand for diagnostic services. We determined the awareness of SRBD amongst Irish paediatricians, examined the provision of sleep services to children throughout the country between 2007 and 2011 and audited diagnostic sleep services in a tertiary centre in 2011. Amongst respondents there was an awareness of SRBD but a poor understanding of diagnostic evaluation with 31/46 (67) referring to inappropriate services. There has been a sharp increase in both diagnostic sleep tests (433-1793 [414]) and in the use of non-invasive ventilation (NIV) (31-186 [627]) for treatment of SRBD between 2007 and 2011. Paediatric sleep services are organized in an ad-hoc manner nationally with significant service variation. The use of domiciliary overnight oximetry reduced the requirement for more formal polysomnography by 70%.
    • Children with life-limiting conditions: establishing accurate prevalence figures.

      Ling, J; O'Reilly, M; Balfe, J; Quinn, C; Devins, M (Irish Medical Journal, 2015-03)
      Children's palliative care is a new and evolving specialty. In order to ascertain accurate data on the number of children requiring services, a number of countries, including Ireland, have undertaken children's palliative care needs assessments. Regardless of the country of origin, the findings of these needs assessments are very similar. Irish child (0-17 years) population figures indicate that there are approximately 1.2 million children in Ireland 1 . Hampered by ambiguity surrounding definitions and the lack of a national database, currently there are no definitive data on the number of these children living with a life-limiting condition
    • Anthropometric characteristics, high prevalence of undernutrition and weight loss: impact on outcomes in patients with adolescent idiopathic scoliosis after spinal fusion.

      Tarrant, Roslyn C; Nugent, Mary; Nugent, Anne P; Queally, Joseph M; Moore, David P; Kiely, Patrick J; Dept. of Orthopaedic Surgery, Our Lady's Children's Hospital, Crumlin, Dublin 12 (SpringerLink, 2015-02-01)
      Abnormal anthropometry including comparably lower weight and body mass index (BMI) in the adolescent idiopathic scoliosis (AIS) population is increasingly recognised, however, no study has examined postoperative weight loss or its clinical relevance in these relatively thin patients. This study aimed to assess perioperative nutritional status as well as clinically severe involuntary weight loss and its impact on outcomes in patients with AIS undergoing posterior spinal fusion (PSF). A further objective was to compare preoperative anthropometric measurements of the current AIS cohort with healthy controls.
    • Sweet syndrome revealing systemic lupus erythematosus.

      Quinn, N; MacMahon, J; Irvine, A D; Lowry, C (Irish Medical Journal, 2015-02)
      Sweet Syndrome is an acute inflammatory skin eruption which is rare in children. We report a case of childhood Systemic Lupus Erythematosus (SLE) that presented with Sweet syndrome. This case is a unique presentation of a common disorder which provides a new facet for the differential diagnosis of SLE in children. It is also the first paediatric case to be reported in a Caucasian child.
    • Sickle cell disease: time for a targeted neonatal screening programme.

      Gibbons, C; Geoghegan, R; Conroy, H; Lippacott, S; O'Brien, D; Lynam, P; Langabeer, L; Cotter, M; Smith, O; McMahon, C (Irish Medical Journal, 2015-02)
      Ireland has seen a steady increase in paediatric sickle cell disease (SCD). In 2005, only 25% of children with SCD were referred to the haemoglobinopathy service in their first year. A non-funded screening programme was implemented. This review aimed to assess the impact screening has had. All children referred to the haemoglobinopathy service born in Ireland after 2005 were identified. Data was collected from the medical chart and laboratory system. Information was analysed using Microsoft Excel. 77 children with SCD were identified. The median age at antibiotic commencement in the screened group was 56 days compared with 447 days in the unscreened group, p = < 0.0003. 22 (28%) of infants were born in centre's that do not screen and 17 (81%) were over 6 months old at referral, compared with 14 (21%) in the screened group. 6 (27%) of those in the unscreened group presented in acute crisis compared with 2 (3%) in the screened population. The point prevalence of SCD in Ireland is 0.2% in children under 15 yr of African and Asian descent. We identified delays in referral and treatment, which reflect the lack of government funded support and policy. We suggest all maternity units commence screening for newborns at risk of SCD. It is a cost effective intervention with a number needed to screen of just 4 to prevent a potentially fatal crisis.
    • Criteria for evaluating response and outcome in clinical trials for children with juvenile myelomonocytic leukemia.

      Niemeyer, Charlotte M; Loh, Mignon L; Cseh, Annamaria; Cooper, Todd; Dvorak, Christopher C; Chan, Rebecca; Xicoy, Blanca; Germing, Ulrich; Kojima, Seiji; Manabe, Atsushi; et al. (Haematologica, 2015-01)
      Juvenile myelomonocytic leukemia is a rare myeloproliferative disease in young children. While hematopoietic stem cell transplantation remains the only curative therapeutic option for most patients, children with juvenile myelomonocytic leukemia increasingly receive novel agents in phase I-II clinical trials as pre-transplant therapy or therapy for relapse after transplantation. However, response criteria or definitions of outcome for standardized evaluation of treatment effect in patients with juvenile myelomonocytic leukemia are currently lacking. Here we propose criteria to evaluate the response to the non-transplant therapy and definitions of remission status after hematopoietic stem cell transplantation. For the evaluation of non-transplant therapy, we defined 6 clinical variables (white blood cell count, platelet count, hematopoietic precursors and blasts in peripheral blood, bone marrow blast percentage, spleen size and extramedullary disease) and 3 genetic variables (cytogenetic, molecular and chimerism response) which serve to describe the heterogeneous picture of response to therapy in each individual case. It is hoped that these criteria will facilitate the comparison of results between clinical trials in juvenile myelomonocytic leukemia.
    • Timing and predictors of return to short-term functional activity in adolescent idiopathic scoliosis after posterior spinal fusion: a prospective study.

      Tarrant, R C; OʼLoughlin, Padhraig F; Lynch, Sam; Queally, Joseph M; Sheeran, Padraig; Moore, David P; Kiely, Patrick J; *Department of Orthopaedic Surgery, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland †National Children's Research Centre, Crumlin, Dublin 12, Ireland ‡Department of Anaesthetics, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland; and §Blackrock Clinic, Blackrock, Dublin, Ireland. (Spine, 2014-08-15)
      Prospective study.
    • Postoperative weight loss and its clinical significance in patients with adolescent idiopathic scoliosis who undergo spinal fusion

      Tarrant, R C; Sheeran P; Noel J; Moore D P (Our Lady's Children's Hospital Crumlin, 2014-06-06)
      TITLE: Postoperative weight loss and its clinical significance in patients with adolescent idiopathic scoliosis who undergo spinal fusion INTRODUCTION Several studies demonstrate a comparably lower preoperative weight and body mass index (BMI) in adolescents with idiopathic scoliosis (AIS); however, no study has quantified unintentional postoperative weight loss, or established its impact on outcomes, in this already ‘thin’ patient population after major spinal deformity surgery. METHODS Seventy seven consecutive and eligible patients with AIS who underwent posterior spinal fusion (PSF) were prospectively follow-up from hospital admission (Jan 2010-April 2012). Pre- and postoperative anthropometric measurements were collected (weight, height, BMI) and unintentional weight loss from admission to hospital discharge recorded. Clinically severe involuntary weight loss during the hospital stay was defined as >10% loss of initial body weight from admission to hospital discharge. Sociodemographic, nutritional and perioperative complication data were obtained. Descriptive statistics using SPSS® were performed. RESULTS Mean age of the cohort was 15 years (SD 1.89). Clinically severe postoperative weight loss >10% was identified in 22 patients (30.6%). Of clinical importance, >10% weight loss was associated with a significantly increased incidence of superficial wound infection (13.6% vs. 2%, P = 0.047). A non-significant trend towards increased minor (81.8% vs. 70%, P = 0.449) and major (9.1% vs. 4%, P = 0.756) complications and a slightly longer hospital stay (median 9.5 days vs. 9 days, P = 0.608) in patients who lost > 10% body weight, was also found. CONCLUSION A high prevalence (30.6%) of clinically severe postoperative weight loss >10% in this AIS cohort, was demonstrated. Significantly increased superficial wound infection rates were observed in patients who lost >10% weight during the hospital stay. While these data require further confirmation, this study suggests that 1) severe postoperative weight loss >10% may be a valuable marker of wound infection risk, and 2) surgical strategies to optimise nutritional status, early detect and prevent severe postoperative weight loss may prove beneficial to modifying wound infection risk in patients with AIS who undergo spinal fusion.
    • Congenital-infantile fibrosarcoma of the foot: avoidance of amputation

      Nason, GJ; Baker, JF; Seoighe, D; Irvine, AD; Mc Dermott, M; Orr, D; Capra, M; Kelly, PM (Irish Medical Journal, 2014-05)
      Congenital-infantile fibrosarcoma is a rare entity with a five year survival rate of over 90%. Surgery is still the most common treatment modality with amputation often necessary. There have been reports supporting the use of neoadjuvant chemotherapy to debulk the tumour in an effort to facilitate limb sparing surgery. We report a case of a newborn who presented with a life threatening haemorrhage from a fibrosarcoma of the foot, successfully treated with Vincristine, Actinomycin and Cyclophosphamide (VAC) chemotherapy alone.
    • Application of the US National Institute of Health (NIH) 2008 guidelines for von Willebrand Disease in a national paediatric comprehensive care centre.[poster]

      Regan, Irene; Burke, Aine; McCormack, Orla; Fox, Christopher; Gleeson, Mary E; Philbin, Brian; Nolan, Beatrice; Our Lady of Lourdes Hospital, Crumlin (Health Service Executive (HSE), 2014-02-28)
    • Doing a Cochrane systematic review: experience of one speech and language therapist [presentation]

      Greene, Zelda; Our Lady’s Children’s Hospital Crumlin (Health Service Executive (HSE), 2014-02-28)
    • Safe and judicious paediatric psychotropic prescribing

      McNicholas, F; Orakwue, N (Irish Medical Journal (IMJ), 2014-02)
      Psychotropic medications are now a well-established and evidenced based treatment for increasing number of child mental health disorders prescribed at increasing frequencies and by increasing number of professional groups. Cliniciansâ perceived levels of competence and standardised monitoring lag behind prescribing practice and should be addressed by regular continuous professional development. A study specific questionnaire on psychotropic prescribing practice in children was mailed to all child psychiatrists and paediatricians working in Ireland and GPs from a selected Dublin CAMHS catchment area. Of the 116 who replied, (39% response rate), antidepressants (58.7%), antipsychotics (57.1%) and ADHD medications (36.5%) were most commonly prescribed. Results suggest increasing trends of monitoring amongst Irish clinicians over time, but with some lack of specificity. Commensurate with the wish of clinicians, ongoing training in paediatric psychopharmacology is considered essential in order to benefit from the increasing advances in pharmacology.
    • Atypical Alstrom syndrome with novel ALMS1 mutations precluded by current diagnostic criteria.

      Casey, Jillian; McGettigan, Paul; Brosnahan, Donal; Curtis, Emma; Treacy, Eileen; Ennis, Sean; Lynch, Sally Ann (2014-02)
      We report on clinical and genetic studies in a non-consanguineous Irish sib-pair with infantile dilated cardiomyopathy and retinopathy. A diagnosis of Alström Syndrome (AS) was considered and diagnostic testing pursued. The Alströms gene (ALMS1) is very large (23 exons) and diagnostic testing of mutational hotspots (exon 6, 8 and 10) was negative. Furthermore the siblings were tall and did not have the typical phenotype of nystagmus, photophobia, obesity or hearing loss and so the AS diagnosis was removed. We then sought to identify the causative gene in this family using whole exome sequencing. Unexpectedly, the exome analysis identified novel compound heterozygous ALMS1 mutations in exon 5 (c.777delT:p.D260fs*26) and exon 20 (c.12145_12146insC:p.S4049fs*36) that segregated with the phenotype. Although the siblings show some clinical overlap with AS, their phenotype is not classical. It is plausible that their atypical presentation may be due to the location of the ALMS1 mutations outside the usual mutational hotspots. Our findings show how atypical cases of AS may be missed under the current diagnostic guidelines and support consideration of complete ALMS1 sequencing in children with two or more features, even if all of the core clinical features of AS are not present.