Oral Health Status of Children Living with Type 1 Diabetes Mellitus

Background: Diabetes is a well-known predisposing factor for oral diseases, so prevention in an early age is mandatory. Objective: To provide oral screening for children living with type 1 diabetes. We aimed to investigate the oral and general health indexes of T1DM children and compare these data to healthy siblings and controls. Methods: In this cross-sectional study, 120 DM patients and 78 siblings, thereafter 80 DM children and 95 controls, took part. A detailed questionnaire, panoramic radiographs, and lateral cephalograms were obtained in every orthodontic consultation. We used Pearson’s chi-square test for statistical analysis and compared the data of the study and control groups. Results: The oral health values of DM children were significantly better (DMF-T 0.83–1.3) than the national average (3.8–4.5). A total of 75% (n = 60) of the children needed orthodontic treatment for orthodontic or skeletal anomalies. The prevalence of skeletal anomalies was significantly (p < 0.05) higher among patients with diabetes mellitus (DM) than in the control group. The frequency of coeliac disease was significantly elevated compared to any literature data (1–3.5%) in the study (15%) and in the control sibling group (13%). Conclusions: Co-morbidities such as CD should get more attention as a prognostic factor for a future higher incidence of diabetes. T1DM children can be motivated and health-conscious patients with excellent oral hygiene and dental status. Orthodontic treatment can help eliminate the oral complications of DM. Special diabetes ambulances may help provide oral care for patients with DM.

Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome

Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma, small stature, skeletal anomalies, sparse brows/lashes, cataracts, and predisposition to cancer. Type 2 RTS patients with biallelic RECQL4 pathogenic variants have multiple skeletal anomalies and a significantly increased incidence of osteosarcoma. Here, we generated RTS patient-derived induced pluripotent stem cells (iPSCs) to dissect the pathological signaling leading to RTS patient-associated osteosarcoma. RTS iPSC-derived osteoblasts showed defective osteogenic differentiation and gain of in vitro tumorigenic ability. Transcriptome analysis of RTS osteoblasts validated decreased bone morphogenesis while revealing aberrantly upregulated mitochondrial respiratory complex I gene expression. RTS osteoblast metabolic assays demonstrated elevated mitochondrial respiratory complex I function, increased oxidative phosphorylation (OXPHOS), and increased ATP production. Inhibition of mitochondrial respiratory complex I activity by IACS-010759 selectively suppressed cellular respiration and cell proliferation of RTS osteoblasts. Furthermore, systems analysis of IACS-010759-induced changes in RTS osteoblasts revealed that chemical inhibition of mitochondrial respiratory complex I impaired cell proliferation, induced senescence, and decreased MAPK signaling and cell cycle associated genes, but increased H19 and ribosomal protein genes. In summary, our study suggests that mitochondrial respiratory complex I is a potential therapeutic target for RTS-associated osteosarcoma and provides future insights for clinical treatment strategies.

High prevalence of anomalies in Nyctimantis brunoi (Anura: Hylidae) from a restinga protected area in southeastern Brazil

In the present study we monitored a population of Nyctimantis brunoi, a species commonly found in restingas of southeastern Brazil. Field activities were carried out in the Parque Nacional da Restinga de Jurubatiba (PNRJ), a protected area located in the northern portion of the state of Rio de Janeiro. Specimens were sampled through a complete species inventory. We analyzed 218 individuals, 32 (14.7%) of which have anomalies. Additionally, a subsample of 15 specimens were radiographed to verify the occurrence of skeletal anomalies not externally detectable and to verify if the classification of anomalies attributed by means of external examination are detectable in the osteological structure of the specimen. There are 12 types of anomalies recognized in this population, three of them only detectable through internal investigation (radiography). We verified that most of anomalies externally detectable were correctly classified when compared to the osteological morphology of the radiographed specimens. Thus, in this investigation, the study of external malformations was capable to detect 60% of the types of anomalies. We conclude that further ecotoxicological and epidemiological studies of the population of N. brunoi in the PNRJ are necessary to establish the origins of anomalies in this species.

High prevalence of variants in skeletal dysplasia associated genes in individuals with short stature and minor skeletal anomalies

Objective: Next generation sequencing (NGS) has expanded the diagnostic paradigm turning the focus to the growth plate. The aim of the study was to determine the prevalence of variants in genes implicated in skeletal dysplasias in probands with short stature and mild skeletal anomalies. Design: Clinical and radiological data were collected from 108 probands with short stature and mild skeletal anomalies. Methods: A customized skeletal dysplasia NGS panel was performed. Variants were classified using ACMG recommendations and Sherloc. Anthropometric measurements and skeletal anomalies were subsequently compared in those with or without an identified genetic defect. Results: Heterozygous variants were identified in 21/108 probands (19.4%). Variants were most frequently identified in ACAN (n=10) and IHH (n=7) whilst one variant was detected in COL2A1, CREBBP, EXT1 and PTPN11. Statistically significant differences (p<0.05) were observed for sitting height/height (SH/H) ratio, SH/H ratio SDS and the SH/H ratio SDS >1 in those with an identified variant compared to those without. Conclusions: A molecular defect was elucidated in a fifth of patients. Thus, the prevalence of mild forms of skeletal dysplasias is relatively high in individuals with short stature and mild skeletal anomalies, with variants in ACAN and IHH accounting for 81% of the cases. An elevated SH/H ratio appears to be associated with a greater probability in detecting a variant, but no other clinical or radiological feature has been found determinant to finding a genetic cause. Currently, we cannot perform extensive molecular studies in all short stature individuals so detailed clinical and radiological phenotyping may orientate which are the candidate patients to obtain worthwhile results. In addition, detailed phenotyping of probands and family members will often aid variant classification.

Renal and Skeletal Anomalies in a Cohort of Individuals With Clinically Presumed Hereditary Nephropathy Analyzed by Molecular Genetic Testing

Background: Chronic kidney disease (CKD) in childhood and adolescence occurs with a median incidence of 9 per million of the age-related population. Over 70% of CKD cases under the age of 25 years can be attributed to a hereditary kidney disease. Among these are hereditary podocytopathies, ciliopathies and (monogenic) congenital anomalies of the kidney and urinary tract (CAKUT). These disease entities can present with a vast variety of extrarenal manifestations. So far, skeletal anomalies (SA) have been infrequently described as extrarenal manifestation in these entities. The aim of this study was to retrospectively investigate a cohort of individuals with hereditary podocytopathies, ciliopathies or CAKUT, in which molecular genetic testing had been performed, for the extrarenal manifestation of SA.Material and Methods: A cohort of 65 unrelated individuals with a clinically presumed hereditary podocytopathy (focal segmental glomerulosclerosis, steroid resistant nephrotic syndrome), ciliopathy (nephronophthisis, Bardet-Biedl syndrome, autosomal recessive/dominant polycystic kidney disease), or CAKUT was screened for SA. Data was acquired using a standardized questionnaire and medical reports. 57/65 (88%) of the index cases were analyzed using exome sequencing (ES).Results: 8/65 (12%) index individuals presented with a hereditary podocytopathy, ciliopathy, or CAKUT and an additional skeletal phenotype. In 5/8 families (63%), pathogenic variants in known disease-associated genes (1x BBS1, 1x MAFB, 2x PBX1, 1x SIX2) could be identified.Conclusions: This study highlights the genetic heterogeneity and clinical variability of hereditary nephropathies in respect of skeletal anomalies as extrarenal manifestation.