Molecular characterization of an embryonal rhabdomyosarcoma occurring in a patient with Kabuki syndrome: report and literature review in the light of tumor predisposition syndromes

Kabuki syndrome is a well-recognized syndrome characterized by facial dysmorphism and developmental delay/intellectual disability and in the majority of patients a germline variant in KMT2D is found. As somatic KMT2D variants can be found in 5-10% of tumors a tumor predisposition in Kabuki syndrome is discussed. So far less than 20 patients with Kabuki syndrome and a concomitant malignancy have been published. Here we report on a female patient with Kabuki syndrome and a c.2558_2559delCT germline variant in KMT2D who developed an embryonal rhabdomyosarcoma (ERMS) at 10 years. On tumor tissue we performed DNA-methylation profiling and exome sequencing (ES). Copy number analyses revealed aneuploidies typical for ERMS including (partial) gains of chromosomes 2, 3, 7, 8, 12, 15, and 20 and 3 focal deletions of chromosome 11p. DNA methylation profiling mapped the case to ERMS by a DNA methylation-based sarcoma classifier. Sequencing suggested gain of the wild-type KMT2D allele in the trisomy 12. Including our patient literature review identified 18 patients with Kabuki syndrome and a malignancy. Overall, the landscape of malignancies in patients with Kabuki syndrome was reminiscent of that of the pediatric population in general. Histopathological and molecular data were only infrequently reported and no report included next generation sequencing and/or DNA-methylation profiling. Although we found no strong arguments pointing towards KS as a tumor predisposition syndrome, based on the small numbers any relation cannot be fully excluded. Further planned studies including profiling of additional tumors and long term follow-up of KS-patients into adulthood could provide further insights

Democracy and human development: issues of conceptualization and measurement

This study attempts to reconcile competing positions in an important debate about the relationship between regime type and human development. We contend that this empirical relationship is contingent upon issues of conceptualization and measurement in democracy. First, the relationship is more likely to be perceived when democracy is measured in a nuanced fashion, taking account of gradations of democracy and autocracy. Second, some aspects of democracy – those associated with competitive elections – are more strongly associated with human development than others. Third, the components of electoral democracy interact in a reinforcing manner. Finally, the impact of democracy on human development is a distal relationship that depends upon a country’s entire regime history. Our approach draws on several new datasets that interrogate change across a century, enhancing empirical leverage on this important question. To measure human development, we employ the Gapminder project, covering most sovereign countries from 1900 to 2012. To measure democracy, we draw on Varieties of Democracy data, which measure democracy in a highly differentiated fashion for most sovereign countries from 1900 to the present. An extensive set of analyses offer strong corroboration for the argument