Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

Purpose: Disorders or differences of sex development (DSDs) are rare congenital conditions characterized by atypical sex development. Despite advances in genomic technologies, the molecular cause remains unknown in 50% of cases. Methods: Homozygosity mapping and whole-exome sequencing revealed an ESR2 variant in an individual with syndromic 46, XY DSD. Additional cases with 46, XY DSD underwent whole-exome sequencing and targeted next-generation sequencing of ESR2. Functional characterization of the identified variants included luciferase assays and protein structure analysis. Gonadal ESR2 expression was assessed in human embryonic data sets and immunostaining of estrogen receptor-beta (ER-beta) was performed in an 8-week-old human male embryo. Results: We identified a homozygous ESR2 variant, c.541_543del p. (Asn181del), located in the highly conserved DNA-binding domain of ER-beta, in an individual with syndromic 46, XY DSD. Two additional heterozygous missense variants, c.251G>T p.(Gly84Val) and c.1277T>G p.(Leu426Arg), located in the N-terminus and the ligand-binding domain of ER-beta, were found in unrelated, nonsyndromic 46, XY DSD cases. Significantly increased transcriptional activation and an impact on protein conformation were shown for the p.(Asn181del) and p.(Leu426Arg) variants. Testicular ESR2 expression was previously documented and ER-beta immunostaining was positive in the developing intestine and eyes. Conclusion: Our study supports a role for ESR2 as a novel candidate gene for 46, XY DSD

A giant ovarian cyst in a neonate with classical 21-hydroxylase deficiency with very high testosterone levels demonstrating a high-dose hook effect

Congenital adrenal hyperplasia (CAH) is a group of disorders affecting the adrenal steroid synthesis. The most common form, 21-hydroxylase deficiency (21-OHD), leads to decreased production of cortisol and aldosterone with increased androgen secretion. In classic CAH, glucocorticoid treatment can be life-saving and serves to bring the symptoms under control. However, the treatment challenge is to effectively control the excess androgen effect by using the lowest possible glucocorticoid dose. Previous studies suggested a relationship between ovarian cyst formation and adrenal androgen excess, but neonatal large ovarian cysts have been very rarely reported in newborns with CAH. Here, we present the unique case of a neonate with classical 21-OHD who underwent surgery for a giant (10x8x7 cm) unilateral solitary ovarian follicular cyst on the 2nd postnatal day. Hormonal evaluation of the patient revealed high-dose hook effect for serum testosterone levels for the first time by a two-site immunoradiometric assay. Possible mechanisms by which androgen excess may cause ovarian cyst formation are discussed. Conflict of interest:None declared

A multidisciplinary approach to an uncommon case of laryngeal leishmaniasis in Turkey

PubMedID: 24947223[No abstract available

Clinical and Laboratory Features of Six Cases of Candida and Dermatophyte Folliculitis and a Review of Published Studies

PubMedID: 26337525Although some studies have investigated the epidemiological characteristics of Malassezia folliculitis (MF), little is known about the clinical features and laboratory characteristics of folliculitis caused by other fungi. In this prospective study, 158 patients with folliculitis were identified, and cytological and mycological examinations were performed. The positive fungal cultures were confirmed using conventional methods, ITS sequencing and HWP1 analysis. Additionally, an in vitro antifungal susceptibility test was performed. Of 158 patients with folliculitis, 65 (41.1 %) were found to have fungal folliculitis. The most common (90.8 %) fungal folliculitis was MF. Non-MF fungal folliculitis was detected in 6 (9.2 %) patients. Four patients were diagnosed with dermatophytic folliculitis (Trichophytonrubrum in three patients and Arthroderma vanbreuseghemii in one patient), and two patients were diagnosed with Candida albicans folliculitis. Although only 5 of the 6 samples were found to be positive via a potassium hydroxide test, all May–Grünwald–Giemsa-stained samples were positive. Both of the C. albicans isolates demonstrated a susceptibility profile to itraconazole, and all four dermatophytes were susceptible to terbinafine. All six patients completely recovered with systemic and topical treatment. This study revealed that dermatophytes and C. albicans are the primary causative agents of non-Malassezia fungal folliculitis. We compared our findings with published reports on fungal folliculitis. © 2015, Springer Science+Business Media Dordrecht.This study was supported in part by the Department of Dermatology, Faculty of Medicine, Ba?kent University Adana Hospital, Adana, Turkey, and the Department of Medical Microbiology, Radboud UMC, Nijmegen, the Netherlands

The relationship between virulence factors and vancomycin resistance among Enterococci collected from food and human samples in Southern Turkey [Türkiye'nin güneyinde gi{dotless}da ve insan örneklerinden toplanan enterokok izolatlari{dotless}ni{dotless}n vankomisin direnci ve virülans faktörleri arasi{dotless}ndaki ilişki]

The aims of this research were to study the prevalence of potential virulence factors, vancomycin resistance and also to evaluate a possible correlation that can exist between vancomycin resistance and potential virulence factors between 51 Enterococcus spp. isolated from food and 50 Enterococcus faecium strains from human in southern Turkey. Identification of the isolates was determined by Vitek-II system. Antimicrobial susceptibility tests were performed by Vitek-II system and disc diffusion method. The presence of vanA and vanB as well as enterococcal virulence genes of cytolysin (cylA), the aggregation substance (asa1), gelatinase (gelE), enterococal surface protein (esp), hyaluronidase (hyl) were investigated by Polymerase Chain Reaction (PCR) method. Haemolysin production was also studied phenotypic method. Apart from one isolate, none of the food originated enterococci were resistant to vancomycin, and none carried vanA and vanB resistance genes. All clinical isolates were resistant to vancomycin and 84% of them carried vanA; 2%, vanB; and 14%, neither vanA nor vanB genes. Except for the cylA gene, all other virulence genes and vancomycin resistance were higher in human strains, and a positive correlation was observed between multivirulence genes and hemolytic activity. For all strains, a positive correlation existed between the esp gene positivity and vancomycin resistance, while for only E. faecium, esp, hyl gene positivity and vancomycin resistance a positive correlation could be seen. Furthermore, "silent cylA" genes were found in two food and one intestinal strains. Based on our findings, we can suggest that virulence increases in parallel to vancomycin resistance, and food may be a potential source for dissemination of gelE, asa1 and hyl virulence genes. Finally, esp and hyl genes presence should carefully be monitored in food originated enterococci

Insights From Long-term Follow-up of a Girl With Adrenal Insufficiency and Sphingosine-1-Phosphate Lyase Deficiency.

Introduction: Sphingosine-1-phosphate lyase (SGPL1) insufficiency syndrome (SPLIS) is a multisystemic disorder which, in the main, incorporates steroid-resistant nephrotic syndrome and primary adrenal insufficiency (PAI). Case Presentation: We present a young girl with a novel homozygous variant in SGPL1, p.D350G, with PAI in the absence of nephrotic syndrome. In the course of 15 years of follow-up she has further developed primary hypothyroidism and while she has progressed through puberty appropriately, ovarian calcifications were noted on imaging. The p.D350G variant results in reduced protein expression of SGPL1. We demonstrate that CRISPR engineered knockout of SGPL1 in human adrenocortical (H295R) cells abrogates cortisol production. Furthermore, while wild-type SGPL1 is able to rescue cortisol production in this in vitro model of adrenal disease, this is not observed with the p.D350G mutant. Conclusion: SGPL1 deficiency should be considered in the differential diagnosis of PAI with close attention paid to evolving disease on follow-up