RESUMEN
The CEP83 protein is an essential part in the first steps of ciliogenesis, causing a ciliopathy if deficient. As a core component of the distal appendages of the centriole, CEP83 is located in almost all cell types and is involved in the primary cilium assembly. Previously reported CEP83 deficient patients all presented with nephronophthisis and kidney dysfunction. Despite retinal degeneration being a common feature in ciliopathies, only one patient also had retinitis. Here, we present two unrelated patients, who both presented with retinitis pigmentosa, without nephronophthisis or any form of kidney dysfunction. Both patients harbor bi-allelic variants in CEP83. This report expands the current clinical spectrum of CEP83 deficiency. For timely diagnosis of CEP83 deficiency, we advocate that CEP83 should be included in gene panels for inherited retinal diseases.
Asunto(s)
Ciliopatías/genética , Proteínas Asociadas a Microtúbulos/genética , Retina/patología , Retinitis Pigmentosa/genética , Niño , Preescolar , Cilios , Ciliopatías/diagnóstico por imagen , Ciliopatías/patología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Riñón/diagnóstico por imagen , Enfermedades Renales/diagnóstico por imagen , Enfermedades Renales/genética , Enfermedades Renales/patología , Masculino , Proteínas Asociadas a Microtúbulos/deficiencia , Retina/diagnóstico por imagen , Retinitis Pigmentosa/diagnóstico por imagen , Retinitis Pigmentosa/patologíaRESUMEN
PURPOSE: Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands. METHODS: Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays. RESULTS: In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband. CONCLUSION: Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases.
Asunto(s)
Degeneración Macular , Transcriptoma , Transportadoras de Casetes de Unión a ATP/genética , Genómica , Humanos , Intrones , Degeneración Macular/genética , Mutación , Linaje , Enfermedad de StargardtRESUMEN
Infectious pediatric uveitis is a rare disease that can cause severe ocular damage if not detected rapidly and treated properly. Additionally, early identification of an infection can protect the child from life-threatening systemic infection. Infectious uveitis can be congenital or acquired and may manifest as a primary ocular infection or as a reactivation. Nevertheless, publications on infectious paediatric uveitis are usually limited to a small number of patients or a case report. So far, most studies on uveitis in children have focused primarily on noninfectious uveitis, and a systematic study on infectious uveitis is lacking. In this review, we summarize the literature on infectious uveitis in pediatric populations and report on the epidemiology, pathophysiology, clinical signs, diagnostic tests, and treatment. We will describe the different possible pathogens causing uveitis in childhood by microbiological group (i.e. parasites, viruses, bacteria, and fungi). We aim to contribute to early diagnosis and management of infectious pediatric uveitis, which in turn might improve not only visual outcome, but also the general health outcome.
Asunto(s)
Uveítis , Humanos , Uveítis/diagnóstico , Uveítis/microbiología , Uveítis/epidemiología , Niño , Infecciones del Ojo/diagnóstico , Infecciones del Ojo/microbiología , Infecciones Bacterianas del Ojo/diagnóstico , Infecciones Bacterianas del Ojo/microbiología , Infecciones Bacterianas del Ojo/epidemiologíaRESUMEN
PURPOSE: To describe the occurrence of anterior uveitis along with systemic manifestations of chronic graft-versus-host disease (GVHD) after nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) in 3 patients with hematologic malignancies. DESIGN: Retrospective small case series. PARTICIPANTS: Three patients who underwent HSCT and 4 age- and gender-matched controls for cytokine analysis in ocular fluid. METHODS: Interventional study of patients who underwent HSCT. Screening for evidence of infectious causes and immunological analysis of ocular fluid samples. MAIN OUTCOME MEASURES: Clinical features of uveitis and results of aqueous analysis. RESULTS: Anterior uveitis developed during an exacerbation of chronic GVHD in 3 patients after allogeneic HSCT for hematologic malignancies. Patients exhibited no abnormalities on extensive uveitis screening, and in addition, serologic and wide-ranging aqueous analysis showed no evidence of recent infections. We observed signs of inflammation in the ocular fluid in 2 of 3 patients by the determination of different cytokines. No other explanation for uveitis was found except the exacerbation of GVHD. Treatment, both systemic and topical, directed to chronic GVHD induced remission of uveitis in all patients along with amelioration of other signs of GVHD. CONCLUSIONS: Anterior uveitis occurred in the wake of the acute exacerbation of chronic GVHD after HSCT and may represent an ocular manifestation of chronic GVHD.
Asunto(s)
Enfermedad Injerto contra Huésped/complicaciones , Uveítis Anterior/etiología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humor Acuoso/metabolismo , Enfermedad Crónica , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Enfermedades Gastrointestinales/complicaciones , Glucocorticoides/uso terapéutico , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucemia Mieloide/terapia , Linfoma de Células del Manto/terapia , Masculino , Persona de Mediana Edad , Mieloma Múltiple/terapia , Estudios Retrospectivos , Enfermedades de la Piel/complicaciones , Trasplante Homólogo , Uveítis Anterior/diagnóstico , Uveítis Anterior/tratamiento farmacológicoRESUMEN
BACKGROUND/AIMS: Studies of uveitis in children have focused primarily on non-infectious causes. To date, no systematic study of infectious uveitis in children has been conducted. We investigate the prevalence of infectious causes of uveitis in children and explore the diagnostic value of analysing aqueous humour. METHODS: Retrospective cohort study in a tertiary referral centre for paediatric uveitis. Medical records of 345 children with uveitis presenting from 1995 through 2010 were reviewed for infectious causes (by serology and aqueous humour analysis). RESULTS: A diagnosis of infectious uveitis was established in 60/345 (17%) children. The most prevalent pathogen was Toxoplasma gondii (36/60; 60%), followed by viral infections (18/60; 30%). The most prevalent viral pathogen was varicella-zoster virus (VZV), representing 7/18 (39%) children. Viral causes were less often bilateral than other infectious causes (p=0.04). Specific IgG serum levels determined in 42/60 (70%) patients, were positive in 41/42 (98%). Aqueous humour was analysed for 24/60 (40%) patients and was positive in 18/24 (75%). CONCLUSIONS: An infectious cause of uveitis was identified in 17% of children with uveitis. T gondii and VZV were the most prevalent pathogens. We recommend analysing the aqueous humour of every child with vision-threatening uveitis of undetermined origin.
Asunto(s)
Infecciones Bacterianas del Ojo/diagnóstico , Infecciones Parasitarias del Ojo/diagnóstico , Infecciones Virales del Ojo/diagnóstico , Uveítis , Adolescente , Animales , Humor Acuoso/microbiología , Humor Acuoso/parasitología , Humor Acuoso/virología , Bacterias/genética , Bacterias/aislamiento & purificación , Niño , Preescolar , Estudios de Cohortes , Infecciones Bacterianas del Ojo/microbiología , Infecciones Parasitarias del Ojo/parasitología , Infecciones Virales del Ojo/virología , Femenino , Humanos , Inmunoglobulina G/sangre , Lactante , Recién Nacido , Masculino , Parásitos/genética , Parásitos/aislamiento & purificación , Prevalencia , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Centros de Atención Terciaria , Uveítis/microbiología , Uveítis/parasitología , Uveítis/virología , Virus/genética , Virus/aislamiento & purificaciónRESUMEN
IMPORTANCE: Tubulointerstitial nephritis and uveitis (TINU) syndrome is characterized by tubulointerstitial and ocular inflammation. Thus far, the value of noninvasive diagnostic tests is not known. OBJECTIVE: To determine whether urinary ß2-microglobulin (ß2M), urinary protein, and serum creatinine have predictive value for detecting TINU syndrome in young patients with uveitis. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study was conducted July 2010 through February 2013 at a tertiary care referral center in Utrecht, the Netherlands. Forty-five consecutive new patients with uveitis aged 22 years or younger were enrolled. EXPOSURES: Urinary ß2M, urinary protein, and serum creatinine were measured prospectively, and the estimated glomerular filtration rate was calculated. MAIN OUTCOMES AND MEASURES: A post hoc analysis was performed to determine whether urinary ß2M, urinary protein, serum creatinine, estimated glomerular filtration rate, and/or pyuria were correlated with definitive and probable cases of TINU syndrome. RESULTS: Eighteen of the 45 patients (40%) in our cohort had elevated urinary ß2M levels, and 10 patients (22%) had elevated serum creatinine levels. Twenty of 43 patients (47%) had proteinuria. Eight of the 45 patients were diagnosed by a pediatric nephrologist as having renal dysfunction that suggested acute interstitial nephritis. Of these 8 patients, 2 were definitively diagnosed as having TINU syndrome (confirmed by renal biopsy). After excluding other causes of renal dysfunction, the remaining 6 patients with uveitis and renal dysfunction fulfilled the criteria of probable TINU syndrome. The 8 patients with definitive or probable TINU syndrome had higher urinary ß2M levels than patients with normal renal function (median ß2M, 1.95 mg/L; 95% CI, 1.26-5.16 mg/L vs 0.20 mg/L; 95% CI, 0.19-0.21 mg/L; P < .001; Mann-Whitney U test). Our analysis revealed that the positive predictive value of increased ß2M combined with increased serum creatinine was 100% for detecting definitive and/or probable TINU syndrome. CONCLUSIONS AND RELEVANCE: These data suggest that urinary ß2M and serum creatinine levels are sensitive and relatively simple diagnostic screening tools for detecting renal dysfunction to diagnose TINU syndrome in young patients with uveitis similar to those evaluated in this study.
Asunto(s)
Creatina/sangre , Nefritis Intersticial/complicaciones , Uveítis/etiología , Microglobulina beta-2/orina , Adolescente , Biomarcadores/sangre , Biomarcadores/orina , Biopsia , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Riñón/patología , Masculino , Nefritis Intersticial/diagnóstico , Nefritis Intersticial/metabolismo , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Síndrome , Uveítis/diagnóstico , Uveítis/metabolismo , Adulto JovenRESUMEN
PURPOSE: To investigate the clinical characteristics of childhood uveitis leading to visual impairment or blindness. METHODS: In this descriptive study, we reviewed data from the medical records of 58 children with visual impairment or blindness due to childhood uveitis, which were seen at an institute for visually impaired patients (Bartiméus) between January 1981 and December 2012, in a retrospective, cross-sectional manner. RESULTS: Thirty-two of the 58 children (55%) were visually impaired and 26 (45%) were legally blind. Uveitis was posterior in 76% of all cases. Infectious uveitis represented 74% of all cases, of which 86% was congenital. Five patients (9%) had uveitis related to a systemic disease, and ten patients (17%) had idiopathic uveitis. There was a decrease in infectious causes over the last decades (p = 0.04) and an increase in idiopathic uveitis (p < 0.01), but the rate of children with posterior uveitis remained constant. There was an overall decrease in the number of children with uveitis referred to Bartiméus. The number of ocular complications at the time of intake was higher in children with acquired disease compared with congenital diseases (p < 0.01), as it was in children with non-infectious uveitis compared with infectious uveitis (p = 0.04). Most comorbidities that were noted were seen in children with infectious uveitis. CONCLUSION: Most patients suffering from visual impairment or blindness due to childhood uveitis had posterior and/or infectious uveitis, mostly congenital. There is a shift in causes which shows a decrease in infectious causes and an increase in idiopathic causes.
Asunto(s)
Ceguera/epidemiología , Uveítis/diagnóstico , Baja Visión/epidemiología , Personas con Daño Visual/estadística & datos numéricos , Niño , Preescolar , Estudios Transversales , Infecciones del Ojo/congénito , Infecciones del Ojo/diagnóstico , Femenino , Humanos , Lactante , Masculino , Países Bajos/epidemiología , Estudios Retrospectivos , Uveítis/congénito , Agudeza VisualRESUMEN
IMPORTANCE: It is essential to have insights into the risk of ocular involvement after hematopoietic stem cell transplantation (HSCT) in the pediatric population because young and severely ill children are unaware of their ocular problems. OBJECTIVE: To study the development of ocular complications in children within 1 year after HSCT. DESIGN AND SETTING: This prospective study includes all consecutive patients who had undergone an HSCT at the Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands, in 2009 and 2010. PARTICIPANTS: Forty-nine consecutive patients underwent systematic ophthalmologic evaluations before HSCT, before leaving the HSCT unit after HSCT, and 3, 6, and 12 months after HSCT. Additional examinations were performed during systemic viral reactivations. MAIN OUTCOME MEASURE: Development of ocular complications, including uveitis, hemorrhagic complications, optic disc edema, and dry eye syndrome. RESULTS: Thirteen patients (27%) developed an ocular complication after HSCT. These complications included DES (n = 7 [14%]), (sub)retinal hemorrhage (n = 6 [12%]), optic disc edema (n = 3 [6%]), chorioretinal lesions (n = 2 [4%]), vitritis (n = 1 [2%]), and increased intraocular pressure (n = 1 [2%]). Median time to the development of dry eye syndrome was 5 months after HSCT, whereas all other ocular complications were detected within the first 3 months after HSCT. In most cases, the symptoms were mild and self-limiting. Children with malignant disease had a higher risk of the development of ocular complications compared with children with nonmalignant disease. CONCLUSIONS AND RELEVANCE: Ocular complications in pediatric HSCT patients are common, although mostly mild. The risk of viral uveitis development during systemic viral reactivations is low; however, the potential risk of vision-threatening complications in this population cannot be ruled out.
Asunto(s)
Oftalmopatías/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adolescente , Niño , Preescolar , Coriorretinitis/diagnóstico , Coriorretinitis/etiología , Síndromes de Ojo Seco/diagnóstico , Síndromes de Ojo Seco/etiología , Oftalmopatías/diagnóstico , Infecciones Virales del Ojo/diagnóstico , Infecciones Virales del Ojo/etiología , Femenino , Enfermedades Hematológicas/tratamiento farmacológico , Humanos , Lactante , Masculino , Hipertensión Ocular/diagnóstico , Hipertensión Ocular/etiología , Papiledema/diagnóstico , Papiledema/etiología , Estudios Prospectivos , Hemorragia Retiniana/diagnóstico , Hemorragia Retiniana/etiología , Trasplante Homólogo , Uveítis/diagnóstico , Uveítis/etiología , Adulto JovenRESUMEN
PURPOSE: To determine the prevalence and manifestations of ocular graft-versus-host disease (GvHD) after allogeneic stem cell transplantation (allo-SCT). METHODS: Prospective study of 101 consecutive patients who received allo-SCT from 2004 to 2007. All patients received ophthalmologic examination for 3 months after allo-SCT, and those with ocular complaints were evaluated at 12 and 24 months thereafter. We registered ophthalmologic and hematological data, including the indication for allo-SCT, occurrence of systemic and ocular GvHDs, ocular manifestations, and various ocular treatments. RESULTS: Over time, ocular GvHD developed in 54% of patients and consisted mainly of dry eyes and conjunctivitis, which increased in severity during follow-up; blepharitis and uveitis were less often encountered. Acute systemic GvHD, especially the involvement of mouth and skin, was strongly associated with ocular GvHD at 3 months (P = 0.000). Chronic GvHD was associated with the occurrence of ocular GvHD (P = 0.000), especially with the development of the dry eye. Although eye symptoms affecting activities of daily living were reported in 24 of 54 patients (44%) and 16 of 54 patients (30%) experienced temporary loss of visual acuity of more than 2 Snellen lines, only 1 developed permanent unilateral loss (counting fingers) because of ischemic vasculopathy. Cataract development was not encountered, and only 1 eye developed intraocular infection. CONCLUSION: Ocular GvHD develops in a substantial part of patients after allo-SCT and decreases the activities of daily living.