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Inherited platelet disorders are a heterogeneous group of rare diseases, caused by inherited defects in platelet production and/or function. Their genetic diagnosis would benefit clinical care, prognosis and preventative treatments. Until recently, this diagnosis has usually been performed via Sanger sequencing of a limited number of candidate genes. High-throughput sequencing is revolutionizing the genetic diagnosis of diseases, including bleeding disorders. We have designed a novel high-throughput sequencing platform to investigate the unknown molecular pathology in a cohort of 82 patients with inherited platelet disorders. Thirty-four (41.5%) patients presented with a phenotype strongly indicative of a particular type of platelet disorder. The other patients had clinical bleeding indicative of platelet dysfunction, but with no identifiable features. The high-throughput sequencing test enabled a molecular diagnosis in 70% of these patients. This sensitivity increased to 90% among patients suspected of having a defined platelet disorder. We found 57 different candidate variants in 28 genes, of which 70% had not previously been described. Following consensus guidelines, we qualified 68.4% and 26.3% of the candidate variants as being pathogenic and likely pathogenic, respectively. In addition to establishing definitive diagnoses of well-known inherited platelet disorders, high-throughput sequencing also identified rarer disorders such as sitosterolemia, filamin and actinin deficiencies, and G protein-coupled receptor defects. This included disease-causing variants in DIAPH1 (n=2) and RASGRP2 (n=3). Our study reinforces the feasibility of introducing high-throughput sequencing technology into the mainstream laboratory for the genetic diagnostic practice in inherited platelet disorders., This study was supported by research grants from the Gerencia Regional de Salud (GRS 1370/A/16), ISCIII & Feder (PI14/01956), CIBERER CB15/00055, Fundación Séneca (19873/GERM/15) and Sociedad Española de Trombosis y Hemostasia (SETH). SPW holds a British Heart Foundation chair.

Respiratory syncytial virus (RSV) infection is common in young children, but only a few develop severe bronchiolitis. The relationship between bronchiolitis, asthma, and atopy has been debated for a long time, but the pathogenesis of wheezing remains unclear. A Th1 and Th2-type lymphocyte imbalance seems to be involved in asthma and atopic disease. Serum interleukin-12 (IL-12), IL-10, and soluble CD30 (sCD30) levels were measured by enzyme-linked immunosorbent assay (ELISA) in 23 cord blood samples kept frozen since birth: 11 from normal term newborns who several months later were admitted to the hospital with bronchiolitis, and 12 from newborns who did not develop the disease (controls). The study was also performed on 28 additional children (1–16 months old) suffering an episode of acute bronchiolitis. IL-12 was clearly increased in all cases at birth, but newborns who later developed bronchiolitis showed low IL-12 levels in cord blood compared to newborns who did not develop the disease (median 295 vs. 507 pg/mL; P = 0.001). sCD30 levels were also decreased in the first group (15 vs. 26 U/mL; P = 0.007). During episodes of bronchiolitis, a clear rise of IL-12, IL-10, and sCD30 was observed. None of the factors studied in the acute phase showed statistical differences in children who were later readmitted to the hospital due to repeated wheezing crises. Children who develop acute bronchiolitis with wheezing may have an immunological imbalance that is expressed at the time of delivery by a lower concentration of serum IL-12. Pediatr Pulmonol. 1999; 28:175–180. © 1999 Wiley-Liss, Inc.

Purpose To describe the diagnosis and management of Coats disease in a patient with Fanconi anemia. Methods Case report. Results A 12-year-old girl with Fanconi anemia developed Coats disease. Retinal vasculature anomalies are present in both diseases; however, differential diagnosis in this case could be based on the presence of telangiectasias, which are typical of Coats disease, and the absence of perivascular sheathing, usually described in the uncommon retinal manifestations of Fanconi anemia. The stage 4 Coats disease was managed with intravitreal bevacizumab injections and later pars plana vitrectomy with silicone oil tamponade surgery, which prevented enucleation despite visual loss. Conclusions Patients with Fanconi anemia can have retinal vasculature anomalies that are not necessarily related to this systemic anomaly. In this case, the retinal alterations were related to advanced Coats disease stage, which was successfully treated, and enucleation of the affected eye was not necessary.