RESUMEN
Coats plus (CP) can be caused by mutations in the CTC1 component of CST, which promotes polymerase α (polα)/primase-dependent fill-in throughout the genome and at telomeres. The cellular pathology relating to CP has not been established. We identified a homozygous POT1 S322L substitution (POT1(CP)) in two siblings with CP. POT1(CP)induced a proliferative arrest that could be bypassed by telomerase. POT1(CP)was expressed at normal levels, bound TPP1 and telomeres, and blocked ATR signaling. POT1(CP)was defective in regulating telomerase, leading to telomere elongation rather than the telomere shortening observed in other telomeropathies. POT1(CP)was also defective in the maintenance of the telomeric C strand, causing extended 3' overhangs and stochastic telomere truncations that could be healed by telomerase. Consistent with shortening of the telomeric C strand, metaphase chromosomes showed loss of telomeres synthesized by leading strand DNA synthesis. We propose that CP is caused by a defect in POT1/CST-dependent telomere fill-in. We further propose that deficiency in the fill-in step generates truncated telomeres that halt proliferation in cells lacking telomerase, whereas, in tissues expressing telomerase (e.g., bone marrow), the truncations are healed. The proposed etiology can explain why CP presents with features distinct from those associated with telomerase defects (e.g., dyskeratosis congenita).
Asunto(s)
Ataxia/genética , Neoplasias Encefálicas/genética , Calcinosis/genética , Quistes del Sistema Nervioso Central/genética , Leucoencefalopatías/genética , Espasticidad Muscular/genética , Mutación/genética , Enfermedades de la Retina/genética , Convulsiones/genética , Acortamiento del Telómero/genética , Proteínas de Unión a Telómeros/genética , Telómero/genética , Telómero/patología , Aminopeptidasas/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Células Cultivadas , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/metabolismo , Femenino , Humanos , Metafase , Unión Proteica , Serina Proteasas/metabolismo , Complejo Shelterina , Transducción de Señal , Telómero/metabolismo , Homeostasis del Telómero/genéticaRESUMEN
BACKGROUND/AIMS: A Bitot spot is a conjunctival lesion, classically associated with severe vitamin A deficiency. In this paediatric series, we describe conjunctival lesions indistinguishable from Bitot spots, seen in the presence of normal vitamin A levels. METHODS: This descriptive case series was performed by retrospective review of case notes, including all patients with Bitot-like spots found to have normal serum vitamin A levels, seen at the Hospital for Sick Children, Toronto, between 2006 and 2016. Data collected included age at presentation, ophthalmic and systemic diagnoses, and the presence of recognised genetic mutations. Histopathology was reviewed in one case. RESULTS: Ten patients with Bitot-like spots with laboratory-confirmed normal serum vitamin A levels were identified. The conjunctival lesions were indistinguishable clinically and histopathologically from classic Bitot spots and were noted to occur in a range of anterior segment pathologies, including aniridia, WAGR syndrome, Axenfeld-Rieger syndrome, and blepharokeratoconjunctivitis. CONCLUSIONS: Bitot-like spots are found in children with a number of anterior segment pathologies in the absence of vitamin A deficiency.
Asunto(s)
Anomalías del Ojo , Enfermedades Hereditarias del Ojo , Deficiencia de Vitamina A , Segmento Anterior del Ojo , Niño , Anomalías del Ojo/complicaciones , Humanos , Vitamina A , Deficiencia de Vitamina A/complicacionesAsunto(s)
Coagulación con Láser , Desprendimiento de Retina , Retinopatía de la Prematuridad , Humanos , Desprendimiento de Retina/cirugía , Desprendimiento de Retina/diagnóstico , Desprendimiento de Retina/etiología , Retinopatía de la Prematuridad/cirugía , Retinopatía de la Prematuridad/diagnóstico , Coagulación con Láser/métodos , Coagulación con Láser/efectos adversos , Recién Nacido , Exudados y Transudados , Edad Gestacional , Masculino , FemeninoRESUMEN
PURPOSE: To describe refractive and visual outcomes of pediatric traumatic cataract requiring surgery and evaluate the factors influencing success. SETTING: Hospital for Sick Children, Toronto, Ontario, Canada. DESIGN: Retrospective case series. METHODS: Charts of children having lensectomy for traumatic cataract between January 1, 2000, and June 30, 2015, were reviewed for demographic information, visual and refractive outcomes, complications, and surgical details. RESULTS: One hundred six children (mean age 7.6 years ± 3.9 [SD]) were included. The median follow-up was 41 months (range 3 to 155 months). Seventy-nine children had open-globe injuries and 27 had closed-globe injuries. Patients with open-globe injuries were younger than those with closed-globe injuries (mean age 6.9 versus 10.4 years; P < .05). The final corrected distance visual acuity (CDVA) was 20/40 or better in 47 children. In the 94 children who had intraocular lens placement, 54% with open-globe injuries and 55% with closed-globe injuries achieved a mean absolute prediction error of 1.0 diopter or less in the early postoperative period. Open-globe injuries and amblyopia were associated with worse visual outcomes (odds ratio [OR], 2.8 and P = .03 versus OR, 2.4 and P = .04) and refractive outcomes (OR, 3.1 and P = .02 versus OR, 3.8 and P = .04). Age younger than 5 years was associated with worse refractive outcomes (OR, 2.88; P = .02). CONCLUSIONS: Children requiring surgery for traumatic cataract can have good visual and refractive outcomes. Those with open-globe and those with closed-globe injuries both had good early postoperative refractive accuracy. Sixty-three percent of children with closed-globe injuries attained a CDVA of 20/40 or better at the final follow-up.