RESUMO
OBJECTIVE: To describe the clinical features, therapeutic interventions, and patient outcomes of gastrointestinal (GI) hemorrhage in individuals with a telomere biology disorder, including dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome, Revesz syndrome, and Coats plus. STUDY DESIGN: Clinical Care Consortium for Telomere Associated Ailments members were invited to contribute data on individuals with telomere biology disorders at their institutions who experienced GI bleeding. Patient demographic, laboratory, imaging, procedural, and treatment information and outcomes were extracted from the medical record. RESULTS: Sixteen patients who experienced GI hemorrhage were identified at 11 centers. Among 14 patients who underwent genetic testing, 8 had mutations in TINF2, 4 had mutations in CTC1 or STN1, and 1 patient each had a mutation in TERC and RTEL1. Ten patients had a history of hematopoietic cell transplantation. The patients with Coats plus and those without Coats plus had similar clinical features and courses. Angiodysplasia of the stomach and/or small bowel was described in 8 of the 12 patients who underwent endoscopy; only 4 had esophageal varices. Various medical interventions were trialed. No single intervention was uniformly associated with cessation of bleeding, although 1 patient had a sustained response to treatment with bevacizumab. Recurrence was common, and the overall long-term outcome for affected patients was poor. CONCLUSIONS: GI bleeding in patients with telomere biology disorders is associated with significant morbidity and with vascular ectasias rather than varices.
Assuntos
Hemorragia Gastrointestinal/etiologia , Telômero/genética , Adolescente , Adulto , Ataxia/complicações , Ataxia/genética , Doenças Ósseas Metabólicas/complicações , Doenças Ósseas Metabólicas/genética , Medula Óssea/anormalidades , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/genética , Calcinose/complicações , Calcinose/genética , Cistos do Sistema Nervoso Central/complicações , Cistos do Sistema Nervoso Central/genética , Criança , Pré-Escolar , Disceratose Congênita/complicações , Disceratose Congênita/genética , Feminino , Retardo do Crescimento Fetal/genética , Hemorragia Gastrointestinal/genética , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Leucoencefalopatias/complicações , Leucoencefalopatias/genética , Masculino , Microcefalia/complicações , Microcefalia/genética , Espasticidade Muscular/complicações , Espasticidade Muscular/genética , Mutação , Retina , Doenças Retinianas/complicações , Doenças Retinianas/genética , Convulsões/complicações , Convulsões/genética , Telômero/metabolismo , Telômero/patologia , Adulto JovemRESUMO
BACKGROUND: Efficacy data from adult ulcerative colitis (UC) clinical trials are often extrapolated for pediatric prescribing. Consequently, it is important to understand similarities/differences in pediatric and adult UC. Pediatric UC tends to have more extensive disease at presentation, yet genetic studies have not detected pathways that distinguish the populations, and differences in mucosal gene expression between adult and pediatric UC are not well characterized. METHODS: Using colonic microarray data from a phase 3 trial of golimumab in adult UC (87 UC; 21 healthy), the GSE10616 pediatric dataset (10 UC; 11 healthy), and a phase 1B trial of golimumab in pediatric UC (nâ=â19), UC expression profiles were compared and unique genes were defined as those with significant changes (|FC|>2×, adjusted Pâ<â0.05) in one population, but not the other (|FC|â<â1.2×, adjusted P > 0.05). Pathway and upstream regulator analyses were performed. Profiles by disease extent (extensive [pancolitis] vs limited [left-sided] involvement) were compared within each population. RESULTS: Pediatric and adult disease profiles overlapped substantially, with â¼50% to 75% overlap, depending on the fold-change cutoff used. Conversely, <10% of the disease profiles were unique to each population. Similar canonical pathways were enriched in both datasets. Predicted upstream regulators were also concordant, including lipopolysaccharide, interleukin-1ß, and tumor necrosis factor-α. Expression profiles of extensive UC were indistinguishable from those of patients with limited involvement in each population. CONCLUSIONS: The UC gene expression landscape is shared by adults and children, independent of disease extent. This supports extrapolation of efficacy from adults to children in developing new therapies for UC.