The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1

PURPOSE: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients. METHODS: STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients. RESULTS: Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61 %). Out of 39 familial cases from 11 families, 26 patients (67 %) from 9 families and out of 18 sporadic cases, 9 patients (50 %) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients. CONCLUSION: STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing

Boston KPro Type I: Vitreoretinal Considerations

Posterior segment complications are seen in a significant number of eyes having a keratoprosthesis (KPro) and are associated with poor visual outcomes. As the use of KPro increases dramatically, so too does the frequency of posterior segment complications seen by the vitreoretinal surgeon in this patient population, as well as the importance of addressing them expeditiously. Special consideration in diagnostic imaging and surgical planning is required in addressing the most common complications: retroprosthetic membrane (RPM), retinal detachments (RD) and other vitreous pathology, hypotony, glaucoma, epiretinal membranes (ERM), endophthalmitis, and vascular complications. This chapter seeks to summarize the diagnosis and treatment of each of these entities in the setting of KPro

Boston Keratoprosthesis Type II: Indications, Techniques, Outcomes, and Management

Implantation of a keratoprosthesis device is indicated for the visual rehabilitation of patients with corneal blindness in whom a standard corneal allograft would likely fail. The Boston keratoprosthesis type I device is a collar button-shaped device, composed of polymethyl methacrylate and titanium, whereas the type II device has an additional anterior extension that allows for implantation through surgically closed eyelids. The type I device is used in patients with intact eyelids, normal blink, and adequate tear film. The type II device is reserved for patients with abnormal lid function and tear secretion, forniceal foreshortening, and ocular surface keratinization. Herein, we focus on the indications, preoperative assessment, surgical technique, and postoperative care for the Boston keratoprosthesis type II and provide advice on management of complications