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NR5A1/SF-1 (Steroidogenic factor-1) variants may cause mild to severe differences of sex development (DSD) or may be found in healthy carriers. The NR5A1/SF-1 c.437G>C/p.Gly146Ala variant is common in individuals with a DSD and has been suggested to act as a susceptibility factor for adrenal disease or cryptorchidism. Since the allele frequency is high in the general population, and the functional testing of the p.Gly146Ala variant revealed inconclusive results, the disease-causing effect of this variant has been questioned. However, a role as a disease modifier is still possible given that oligogenic inheritance has been described in patients with NR5A1/SF-1 variants. Therefore, we performed next generation sequencing (NGS) in 13 DSD individuals harboring the NR5A1/SF-1 p.Gly146Ala variant to search for other DSD-causing variants and clarify the function of this variant for the phenotype of the carriers. Panel and whole-exome sequencing was performed, and data were analyzed with a filtering algorithm for detecting variants in NR5A1- and DSD-related genes. The phenotype of the studied individuals ranged from scrotal hypospadias and ambiguous genitalia in 46,XY DSD to opposite sex in both 46,XY and 46,XX. In nine subjects we identified either a clearly pathogenic DSD gene variant (e.g. in AR) or one to four potentially deleterious variants that likely explain the observed phenotype alone (e.g. in FGFR3, CHD7). Our study shows that most individuals carrying the NR5A1/SF-1 p.Gly146Ala variant, harbor at least one other deleterious gene variant which can explain the DSD phenotype. This finding confirms that the NR5A1/SF-1 p.Gly146Ala variant may not contribute to the pathogenesis of DSD and qualifies as a benign polymorphism. Thus, individuals, in whom the NR5A1/SF-1 p.Gly146Ala gene variant has been identified as the underlying genetic cause for their DSD in the past, should be re-evaluated with a NGS method to reveal the real genetic diagnosis.

Disorders/differences of sex development (DSD) are the result of a discordance between chromosomal, gonadal, and genital sex. DSD may be due to mutations in any of the genes involved in sex determination and development in general, as well as gonadal and/or genital development specifically. MAMLD1 is one of the recognized DSD genes. However, its role is controversial as some MAMLD1 variants are present in normal individuals, several MAMLD1 mutations have wild-type activity in functional studies, and the Mamld1-knockout male mouse presents with normal genitalia and reproduction. We previously tested nine MAMLD1 variants detected in nine 46, XY DSD patients with broad phenotypes for their functional activity, but none of the mutants, except truncated L210X, had diminished transcriptional activity on known target promoters CYP17A1 and HES3. In addition, protein expression of MAMLD1 variants was similar to wild-type, except for the truncated L210X. We hypothesized that MAMLD1 variants may not be sufficient to explain the phenotype in 46, XY DSD individuals, and that further genetic studies should be performed to search for additional hits explaining the broad phenotypes. We therefore performed whole exome sequencing (WES) in seven of these 46, XY patients with DSD and in one 46, XX patient with ovarian insufficiency, who all carried MAMLD1 variants. WES data were filtered by an algorithm including disease-tailored lists of MAMLD1-related and DSD-related genes. Fifty-five potentially deleterious variants in 41 genes were identified; 16/55 variants were reported in genes in association with hypospadias, 8/55 with cryptorchidism, 5/55 with micropenis, and 13/55 were described in relation with female sex development. Patients carried 1-16 variants in 1-16 genes together with their MAMLD1 variation. Network analysis of the identified genes revealed that 23 genes presented gene/protein interactions with MAMLD1. Thus, our study shows that the broad phenotypes of individual DSD might involve multiple genetic variations contributing towards the complex network of sexual development. This work was supported by grants of the Swiss National Science Foundation (http://www.snf.ch) (320030-146127) to CF, the Instituto de Salud Carlos III (www.isciii.es/; Madrid, Spain) Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER, http://www.ciberer.es/) U-712 to MF-C, the Agency for Management of University and Research Grants (AGAUR; agaur.gencat.cat), Barcelona, Spain (2009SGR31) to LA, and by the Beatriu de Pinos Fellowship 2014 BP-B 00145 (AGAUR, Catalonia, Spain), the Instituto de Salud Carlos III (www.isciii.es/; Madrid, Spain) Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER; http://www.ciberer.es/) U-712 to NC.

This study evaluated the patterns of substance use in a large sample of male-to-female (MtoF) and female-to-male (FtoM) transsexuals. A total of 251 transsexual subjects (163 MtoF and 88 FtoM), attended in the Catalonia Gender Unit, completed self-administrated questionnaires on consumption of alcohol, tobacco, cannabis, cocaine, opioids, and designer drugs. Results were compared with the general population in Catalonia using data from the National Health Service (EDADES 2013 study). Current consumption of alcohol (70.1%), tobacco (46.2%), and cannabis (16.3%) among transsexuals was similar when compared with men (72.1%, 42.1%, 12.8%) and increased when compared with women (57.6%, 35.2%, 5%); the consumption between MtoF and FtoM subgroups was similar. The use of cocaine was almost ten times more prevalent in the MtoF subgroup than in the FtoM subgroup (1.1%), and in general population (less than 1%). Only a few reported uses of opioids and designer drugs. In conclusion, the substance use among transsexuals, except for the use of cocaine, was similar between MtoF and FtoM subgroups, and resembled the consumption prevalence among men in the general population. The proportion of cocaine consumers in the MtoF subgroup was up to ten times higher than in other subgroups.

Disorders/differences of sex development (DSD) are the result of a discordance between chromosomal, gonadal, and genital sex. DSD may be due to mutations in any of the genes involved in sex determination and development in general, as well as gonadal and/or genital development specifically. MAMLD1 is one of the recognized DSD genes. However, its role is controversial as some MAMLD1 variants are present in normal individuals, several MAMLD1 mutations have wild-type activity in functional studies, and the Mamld1-knockout male mouse presents with normal genitalia and reproduction. We previously tested nine MAMLD1 variants detected in nine 46,XY DSD patients with broad phenotypes for their functional activity, but none of the mutants, except truncated L210X, had diminished transcriptional activity on known target promoters CYP17A1 and HES3. In addition, protein expression of MAMLD1 variants was similar to wild-type, except for the truncated L210X. We hypothesized that MAMLD1 variants may not be sufficient to explain the phenotype in 46,XY DSD individuals, and that further genetic studies should be performed to search for additional hits explaining the broad phenotypes. We therefore performed whole exome sequencing (WES) in seven of these 46,XY patients with DSD and in one 46,XX patient with ovarian insufficiency, who all carried MAMLD1 variants. WES data were filtered by an algorithm including disease-tailored lists of MAMLD1-related and DSD-related genes. Fifty-five potentially deleterious variants in 41 genes were identified; 16/55 variants were reported in genes in association with hypospadias, 8/55 with cryptorchidism, 5/55 with micropenis, and 13/55 were described in relation with female sex development. Patients carried 1-16 variants in 1-16 genes together with their MAMLD1 variation. Network analysis of the identified genes revealed that 23 genes presented gene/protein interactions with MAMLD1. Thus, our study shows that the broad phenotypes of individual DSD might involve multiple genetic variations contributing towards the complex network of sexual de

The Psychosocial Aspects of Diabetes (PSAD) Study Group is an official Study Group of the European Association for the Study of Diabetes (EASD). AIMS: Evidences of benefits of telemedicine in T1DM patients on continuous subcutaneous insulin infusion (CSII) treatment are limited. Aims: 1) to analyse the differences in clinical and psychological variables between subjects with T1DM on CSII treatment who were included in a Telecare (TC) program, and subjects with T1DM on CSII treatment who received Conventional care (CC); 2) Perform a cost analysis of the use of telemedicine in DM1 patients treated with CSII (TC versus CC). METHODS and PARTICIPANTS: Cross-over randomized clinical trial with duration of 18 months. 51 patients signed informed consent. Participants were randomly assigned to receive TC program or CC during 6 months, and after a 3 months wash-out period, patients changed to CC or to TC respectively. TC program included monthly visits using an Internet platform. CC comprised face-to-face visits every three months. Sociodemographic, clinical and psychological data was measured at the beginning and at the end of TC and CC. The direct and indirect costs were also measured. T Student was performed to assess differences between first and last visits in both groups (TC / CC). RESULTS: Patients with telemedicine at the end of treatment, have fewer hyperglycemia / week, less distress and greater adherence. Considering both direct and indirect costs, the cost per treatment (TC / CC) is similar. CONCLUSIONS: Telemedicine has significant implications for clinical and psychological variables and has the same cost (total) than the conventional treatment. Therefore, it can be a useful alternative for treatment of DM1 patients with CSII. However, studies with a larger sample size are needed. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech.