Great Ormond Street Hospital for Children NHS Foundation Trust runs Great Ormond Street Hospital. It is closely associated with University College London (UCL) and in partnership with the UCL Institute of Child Health, which it is located adjacent to, is the largest centre for research and postgraduate teaching in children’s health in Europe. It is part of both the Great Ormond Street Hospital/UCL Institute of Child Health Biomedical Research Centre and the UCL Partners academic health science centre.Great Ormond Street Hospital NHS Trust became a foundation trust on 1 March 2012.
Cerebral folate deficiency refers to neurological disorders associated with a reduced cerebrospinal fluid (CSF) concentration of 5-methyltetrahydrofolate (5-MTHF), arising from primary defects in folate transport or metabolism, or secondarily from acquired or other inherited conditions. Clinical presentation ranges from infancy to adulthood, with manifestations including developmental delay, seizures, cognitive impairment, and neuropsychiatric symptoms. Folate plays a central role in one-carbon metabolism, requiring interaction with other B-vitamins, most notably vitamin B12, to support nucleotide synthesis, methylation reactions, and myelin production. Disruption of folate-dependent pathways contributes to the imaging findings of cerebral folate deficiencies, which include abnormal white matter, calcifications, cerebral or cerebellar atrophy, and in some cases, stroke, or stroke-like lesions. This review outlines folate biochemistry, transport mechanisms into the central nervous system, and associated genetic defects, followed by a discussion of imaging features in primary and secondary cerebral folate deficiencies. Relevant differential diagnoses, particularly cobalamin-related disorders, are also examined. Importantly, many cerebral folate deficiencies are potentially reversible with timely recognition and therapy, underscoring the important role of neuroimaging in diagnosis and follow-up of these disorders.
Abstract Background Chronic disease, including different forms of epidermolysis bullosa (EB), may significantly impair health-related quality of life (HRQoL). To date, HRQoL in specific subtypes of recessive dystrophic EB (RDEB) has not been studied in depth. Objectives To measure HRQoL in a large cohort of individuals with different RDEB subtypes, to explore differences in physical functioning and emotional/psychosocial health scores, and to identify potential correlation with disease severity. Methods The Prospective EB Longitudinal Evaluation Study (PEBLES) is a register study of children and adults with RDEB. Reviews are repeated every 6 months (under 10 years) or annually (10 years and above) with HRQoL assessed using the Quality of Life in Epidermolysis Bullosa (QOLEB), an EB-specific questionnaire, for adult participants and the Pediatric Quality of Life Inventory (PedsQL) generic core scales, version 4.0, for child participants and their parents. Disease severity was measured with the Birmingham EB Severity score (BEBS) and the Instrument for Scoring Clinical Outcomes for EB (iscorEB). Results HRQoL was reported in 335 reviews over a maximum of seven years by 61 participants: severe RDEB (RDEB-S) n = 26, intermediate (RDEB-I) n = 21, inversa (RDEB-Inv) n = 9, pruriginosa (RDEB-Pru) n = 4 and pretibial RDEB n = 1. QOLEB demonstrated a severe impact on HRQoL for all RDEB adults (n = 47), particularly for RDEB-Pru and RDEB-S participants. Total and functioning QOLEB scores correlated with disease severity scores (iscorEB, BEBS) for all RDEB, with a statistically higher impact in RDEB-S compared to RDEB-I and RDEB-Inv. In children (n = 14), those with greater disease severity measured by iscorEB also reported worse HRQoL (PedsQL). In adults and children, physical functioning/health QoL was more severely impacted than emotions/psychosocial health, and HRQoL generally improved with age. Conclusion Our results highlight a significant impact on HRQoL in adults and children with all types of RDEB which generally correlates with disease severity. Relatively less impact on emotional functioning/psychosocial health rather than physical functioning/health scores suggests psychological adaptation from living with RDEB, a lifelong condition which typically presents at or shortly after birth. Further, a relative improvement in HRQoL with age, despite disease progression and increasing severity over time, supports ongoing adaptation throughout life.
Short stature may be caused by a multitude of conditions, including genetic and non-genetic causes. Over the last decade, advances in genetic sequencing technologies have revolutionized our understanding of the underlying physiology of growth and greatly increased our ability to identify genetic etiologies of short stature. The current guideline provides a general overview of the approach to the evaluation of a child with short stature, followed by recommendations identifying factors in the medical and family history, physical examination, radiographic, and laboratory work up which increase the likelihood of identifying a genetic etiology. An algorithm is proposed for the genetic workup of individuals with short stature based on their clinical presentation. The benefits and risks of genetic testing are discussed as well.
PURPOSE:Molecular biomarkers are increasingly used for risk stratification, particularly in up-front surgery settings (Children's Oncology Group trials), whereas in preoperative chemotherapy setting, the ongoing International Society of Pediatric Oncology (SIOP)-Renal Tumor Study Group-2016 UMBRELLA study aims to validate selected biomarkers for future risk-adapted treatment strategies. This systematic review summarizes all literature on the prognostic value of these biomarkers. MATERIALS AND METHODS:A systematic literature review (PubMed and Embase; up to January 2025) included studies with ≥50 de novo Wilms tumors (WTs). Eligible biomarkers included copy number variations; 1q gain, 1p and/or 16q loss of heterozygosity (LOH)/loss, 12 gain, 14q loss, 22 loss, 11p15 LOH/loss of imprinting (LOI), and structural somatic variants (TP53 [and/or 17p loss], MYCN, FBXW7, WT1, WTX, SIX1/SIX2, DROSHA, DGCR8, AMER1, CTNNB1, GPC3, MLLT1, DICER1, DIS3L2). Outcome included relapse-free survival, event-free survival (EFS), and overall survival (OS). Risk of bias was assessed with quality in prognosis studies tool. RESULTS:Low-bias multivariable/stratified analyses identified 1q gain as worse EFS and 1p and/or 16q LOH/loss as worse EFS/OS prognostic factors, in up-front nephrectomy settings. Preoperative chemotherapy settings revealed similar trends with lacking significance. TP53 and MYCN were adverse prognostic in univariate analyses. No prognostic data were available for the remaining variants. CONCLUSION:1q gain and 1p and/or 16q LOH/loss emerge as independent prognostic biomarkers in up-front nephrectomy settings. Evidence remains limited in preoperative chemotherapy settings, particularly when using SIOP-oriented treatment algorithms. Prognostic value of TP53, MYCN, and 11p15 LOH/LOI warrants further validation in both settings. This highlights the need for adequately powered prospective studies, specifically in the preoperative chemotherapy setting, to establish reliable molecular biomarkers.
ABSTRACT:We evaluated long-term outcomes of 288 children with refractory-Langerhans cell histiocytosis (R-LCH) from 26 countries, who were prescribed off-label MAPK inhibitors (MAPKis) according to clinical indications. MAPKi indications included 148 R-risk-organ-positive (R-RO+), 67 R-risk-organ-negative (R-RO-), 13 lung destruction (lung), 9 sclerosing cholangitis (SC), 49 neurodegeneration (ND), and 2 diabetes insipidus (DI) cases. Median ages at diagnosis and MAPKi onset were 1.3 and 2.3 years, respectively, with median follow-up of 3.7 years (1166 person-years). Agents mostly prescribed as monotherapies were 184 prescriptions of vemurafenib, 115 of dabrafenib, 3 of encorafenib, 42 of cobimetinib, 45 of trametinib, and/or 1 prescription of binimetinib; followed 51 times by various chemotherapies or hematopoietic stem-cell transplantation, or 28 times by combined anti-BRAF-anti-MEK. Short-term responses (<8 weeks) ranged from 98% (R-RO+ and R-RO-), to 30% (lung) to none (ND, DI, and SC); although long-term lung and ND responses could be observed. Skin rash was the most frequent adverse event (∼55%), and 7 others included 1 case of cardiomyopathy and 6 of retinitis. Five developed MAPKi-unrelated tumors and 9 patients died. Five-year survival was 98%. After 113 patients with R-LCH discontinued MAPKi, 69 experienced disease reactivation. None of the various empirical maintenance therapies were able to prevent secondary reactivation. Among the 143 assessable patients without ND-LCH at MAPKi onset, 60 developed ND (45%, 5-year risk). MAPKis appeared to be safe and effective in children with R-RO+/RO-LCH, whereas other indications' responses were less frequent or occurred later. Further studies are needed to find effective maintenance-therapy approaches, particularly to prevent frequently observed secondary ND.
