Genetic reanalysis of patients with a difference of sex development carrying the NR5A1/SF-1 variant p.Gly146Ala has discovered other likely disease-causing variations.

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.

Desmoplastic infantile astrocytoma with atypical phenotype, PTEN homozygous deletion and BRAF V600E mutation.

Desmoplastic infantile astrocytoma (DIA) is rare, cystic and solid tumor of infants usually found in superficial cerebral hemispheres. Although DIA is usually benign, uncommon cases bearing malignant histological and aggressive clinical features have been described in the literature. We report a newborn patient who was diagnosed with a DIA and died postresection. Pathologic examination revealed that the main part of the tumor had benign features, but the internal region showed areas with a more aggressive appearance, with higher-proliferative cells, anaplastic GFAP positive cells with cellular polymorphism, necrosis foci, vascular hyperplasia with endothelial proliferation and microtrombosis. Genetic study, performed in both regions of the tumor, showed a BRAF V600E mutation and a homozygous deletion in PTEN, without changes in other relevant genes like EGFR, CDKN2A, TP53, NFKBIA, CDK4, MDM2 and PDGFRA. Although PTEN homozygous deletions are described in gliomas, the present case constitutes the first report of a PTEN mutation in a DIA, and this genetic feature may be related to the malignant behavior of a usually benign tumor. These genetic findings may point at the need of further and deeper genetic characterization of DIAs, in order to better understand the biology of this tumor and to obtain new prognostic approaches, a better clinical management and targeted therapies, especially in malignant cases of DIA.

[Infections in early life as risk factor for coeliac disease]. / Infecciones en la primera infancia como factor de riesgo de enfermedad celiaca.

INTRODUCTION: Among the environmental factors that can affect the pathological response to gluten in coeliac disease (CD), the factors that influence the immune response, such as infections and use of antibiotics, are proposed. Our objective is to determine the relationship between infections in early life and the risk of CD. PATIENTS AND METHODS: A retrospective case-control study, including patients aged 0-16 years with a diagnosis of CD was performed between the years 2014-2018. An analysis was made of documented infections in the first 6 months of life, types of infection (respiratory, gastrointestinal, urinary, others), microorganisms involved, and antibiotic therapy used. RESULTS: A total of 93 coeliac patients, 93 controls, and 237 infectious episodes were registered. Documented infections affected 67.7% of coeliac patients and 50.5% of controls (P = .017), with a mean of 1.49 ± 1.53 episodes in the coeliac group and 1.05 ± 1.5 in the controls (P = .016). Documented infections in the first 6 months of life doubles the risk of developing CD (OR 2.05; 95% CI; 1.13-3.73), with this risk being higher for respiratory infections, which multiply the risk by 2.3 (OR 2.30, 95% CI; 1.28-4.14). Also, having 3 or more respiratory infections in the first 6 months of life multiplied the risk by 2.8 (OR 2.79, 95% CI; 1.03-7.54). No differences were found related to the types of involved microorganism or regarding the use of antibiotics. CONCLUSIONS: Infections in the first 6 months of life increase the risk of developing CD, especially for respiratory infections and, to a greater extent, if 3 or more episodes occur. The use of antibiotics in this period of life has not been related to an increased risk of CD.

Drug-Loaded Biomimetic Ceramics for Tissue Engineering.

The mimesis of biological systems has been demonstrated to be an adequate approach to obtain tissue engineering scaffolds able to promote cell attachment, proliferation, and differentiation abilities similar to those of autologous tissues. Bioceramics are commonly used for this purpose due to their similarities to the mineral component of hard tissues as bone. Furthermore, biomimetic scaffolds are frequently loaded with diverse therapeutic molecules to enhance their biological performance, leading to final products with advanced functionalities. In this review, we aim to describe the already developed bioceramic-based biomimetic systems for drug loading and local controlled release. We will discuss the mechanisms used for the inclusion of therapeutic molecules on the designed systems, paying special attention to the identification of critical parameters that modulate drug loading and release kinetics on these scaffolds.