We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease‐associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine‐responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype–phenotype relations for the WFS1 gene. The presence of biallelic loss‐of‐function variants predicted Wolfram syndrome defined by insulin‐dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%–83%) and specificity of 92% (83%–97%). The presence of minor loss‐of‐function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%–100%]; specificity 78% [73%–82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next‐generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org.
The early presence of a non-autoimmune insulin dependent DM, should alert us of an "infrequent" diabetes syndrome. Wolfram's presumptive diagnosis could be established if juvenile-onset DM occurs concomitantly with OA, and this visual impairment is not attributable to diabetic retinopathy. Despite the long period of evolution of DM and altered values of HbA1c, the prevalence of microvascular complications in the sample are low.
Echogenic intracardiac foci are a second trimester marker associated with aneuploidy in high-risk populations. The objective of this study is to assess the validity of echogenic intracardiac foci for Down syndrome detection in the second trimester ultrasound scan. A systematic search in major bibliographic databases was carried out (MEDLINE, EMBASE, CINAHL). Twenty-five studies about echogenic intracardiac foci were selected for statistical synthesis in this systematic review. Those 25 considered to be relevant were then subjected to critical reading, following the Critical Appraisal Skills Programme criteria, by at least three independent observers. Then, the published articles were subjected to a meta-analysis. A global sensitivity of 21.8% and a 4.1% false positive rate were obtained. The positive likelihood ratio was 5.08 (95% confidence interval, 4.04-6.41). The subgroups analysis did not reveal statistically significant differences. In conclusion, echogenic intracardiac foci as an isolated marker could be a tool to identify-rather than exclude-the high-risk group of Down syndrome, although it should be noted that it shows low sensitivity.
Wolfram Syndrome (WS) is a rare disease (RD) with an estimated prevalence of 1/770,000 inhabitants. It is considered a multisystemic, chronic and progressive disease.WS diagnosis implies devastating consequences at physical, educational and emotional levels. WS is also known by the acronym DIDMOAD, derived from the first letters of the main clinical symptoms: Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness. Rare diseases are characterized by their low prevalence and the lack of knowledge on the pathophysiology and treatment of them. Interestingly, around 80% of RD have a genetic basis, and this fact causes doubts and uncertainties in the couples, about the idea of having another child. The existence of a RD in a family, alters significantly the relationships and the quality of life within the family. The present work remarks the huge value of psychosocial aspects in order to pay an adequate attention to these patients, not only taking care of the clinical aspects. The main purpose of this study has been to ascertain the quality of life of Wolfram’s syndrome affected patients, and its impact in the daily life.
Thyroid hormones are fundamental for growth and bone maturity. Retarded physical and osseous development signals congenital hypothyroidism. This study assessed the evolution of height and bone age and final height after hormone replacement treatment in 25 patients with primary congenital hypothyroidism. Bone ages, measured periodically for 12 years after treatment began, were expressed as standard deviation scores (SDS) corresponding to chronologic age. Heights were expressed as SDS and related to standardized curves and genetic height. All patients experienced height recovery during the first year. Of 19 patients who reached their final height, 16 surpassed the expected mean for genetic height. Bone age accelerated progressively, with total recovery toward the third year, and remained accelerated, reaching +1.43 +/- 1.27 in relation to chronologic age 12 years after hormone replacement began. Thus, early diagnosis and adequate treatment of congenital hypothyroidism improved growth and osseous development, although progressive acceleration of bone age may have limited final height in some children.
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