Paediatric Wolfram syndrome Type 1: should gonadal dysfunction be part of the diagnostic criteria?

AimsWolfram Syndrome Spectrum Disorder (WFS1-SD), in its “classic” form, is a rare autosomal recessive disease with poor prognosis and wide phenotypic spectrum. Insulin dependent diabetes mellitus (DM), optic atrophy (OA) diabetes insipidus (DI) and sensorineural deafness (D) are the main features of WFS1-SD. Gonadal dysfunction (GD) has been described mainly in adults with variable prevalence and referred to as a minor clinical feature. This is the first case series investigating gonadal function in a small cohort of paediatric patients affected by WFS1-SD.MethodsGonadal function was investigated in eight patients (3 male and 5 female) between 3 and 16 years of age. Seven patients have been diagnosed with classic WFS1-SD and one with non-classic WFS1-SD. Gonadotropin and sex hormone levels were monitored, as well as markers of gonadal reserve (inhibin-B and anti-Mullerian hormone). Pubertal progression was assessed according to Tanner staging.ResultsPrimary hypogonadism was diagnosed in 50% of patients (n=4), more specifically 67% (n=2) of males and 40% of females (n=2). Pubertal delay was observed in one female patient. These data confirm that gonadal dysfunction may be a frequent and underdiagnosed clinical feature in WFS1-SD.ConclusionsGD may represent a frequent and earlier than previously described feature in WFS1-SD with repercussions on morbidity and quality of life. Consequently, we suggest that GD should be included amongst clinical diagnostic criteria for WFS1-SD, as has already been proposed for urinary dysfunction. Considering the heterogeneous and elusive presentation of WFS1-SD, this clinical feature may assist in an earlier diagnosis and timely follow-up and care of treatable associated diseases (i.e. insulin and sex hormone replacement) in these young patients

Early and long-term outcomes of minimally invasive mitral valve surgery through right minithoracotomy: a ten-year experience in 1604 patients

The purpose of this thesis is to report and analyse early and long-term outcomes of all patients that underwent minimally invasive mitral valve surgery through right minithoracotomy at Fondazione Toscana Gabriele Monasterio - Ospedale del Cuore. In September 2003 the first patient was operated on using this technique. At the end of December 2013, a total of 1604 consecutive patients had benefited from minimally invasive mitral valve surgery and thus avoided median sternotomy. The mean age was 63±13 years, 770 (48%) patients were female and 218 (13.6%) had previous cardiac operations. The prevailing etiology was degenerative valve disease (n=1114, 70%), followed by functional mitral regurgitation (n=191, 12%), rheumatic disease (n=151, 9.4%), endocarditis (n=80, 5%) and prosthetic dysfunction (3.2%). Repair rate was 71% overall (n=1137) and even higher (82%, n=932) in the degenerative disease subgroup. Techniques included annuloplasty (95%), leafleat resection (63%), neochordae implantation (16%), and sliding plasty (11%). 476 (29%) patients had their valve replaced. Concomitant procedures included tricuspid valve repair (n=234, 14.6%), atrial fibrillation ablation (n=152, 9.5%) and atrial septal defect closure (n=51, 3.2%). Direct aortic cannulation was achieved in 1289 (80.4%) patients. Overall in-hospital mortality was 1.1% (n=19), lower than predicted by EuroSCORE I (median 6%, interquartile range 3-14%). 34 patients (2.1%) required conversion to standard sternotomy, while 32 (2%) had a stroke. Overall survival at 10 years was 88±2% and freedom from reoperation at 10 years was 91±1% for repair and 82±6% for replacement. Freedom from recurrent mitral regurgitation ≥3+ after 5 years was 94±2%. In summary, minimally invasive mitral valve surgery is safe, reproducible, and associated with low mortality and morbidity, high rate of mitral valve repair and excellent long-term results

Scalable GMP-compliant gene correction of CD4+ T cells with IDLV template functionally validated in vitro and in vivo

Hyper-IgM1 is a rare X-linked combined immunodeficiency caused by mutations in the CD40 ligand (CD40LG) gene with a median survival of 25 years, potentially treatable with in situ CD4+ T cell gene editing with Cas9 and a one-size-fits-most corrective donor template. Here, starting from our research-grade editing protocol, we pursued the development of a good manufacturing practice (GMP)-compliant, scalable process that allows for correction, selection and expansion of edited cells, using an integrase defective lentiviral vector as donor template. After systematic optimization of reagents and conditions we proved maintenance of stem and central memory phenotypes and expression and function of CD40LG in edited healthy donor and patient cells recapitulating the physiological CD40LG regulation. We then documented the preserved fitness of edited cells by xenotransplantation into immunodeficient mice. Finally, we transitioned to large-scale manufacturing, and developed a panel of quality control assays. Overall, our GMP-compliant process takes long-range gene editing one step closer to clinical application with a reassuring safety profile