Prader-Willi syndrome: guidance for children and transition into adulthood.

Prader-Willi syndrome (PWS) is a rare orphan disease and complex genetic neurodevelopmental disorder, with a birth incidence of approximately 1 in 10,000-30,000. Management of people with PWS requires a multi-disciplinary approach, ideally through a multi-disciplinary team (MDT) clinic with community support. Hypotonia, poor feeding and faltering growth are characteristic features in the neonatal period, followed by hyperphagia and risk of rapid weight gain later in childhood.

An effective and cost-saving structured education program teaching dynamic glucose management strategies to a socio-economically deprived cohort with type 1 diabetes in a VIRTUAL setting.

Objectives: Compare the clinical and cost-effectiveness of an established face to face (F2F) structured education program to a new remote (VIRTUAL) program teaching dynamic glucose management (DynamicGM) to children and young people with type 1 diabetes (CYPD) using continuous glucose monitoring (CGM). To ascertain the most effective DynamicGM strategies predicting time in range (TIR) (3.9-10.

Clinical characteristics and treatment requirements of children with autosomal recessive pseudohypoaldosteronism.

Introduction: Autosomal recessive forms of pseudohypoaldosteronism are caused by genetic defects in the epithelial sodium channel. Little is known about the long-term outcome and medication needs during childhood and adolescence.

Objective: This study reports a single-centre experience of children affected with this ultra-rare condition over a 37-year period.

DYNAMIC: Dynamic glucose management strategies delivered through a structured education program improves time in range in a socioeconomically deprived cohort of children and young people with type 1 diabetes with a history of hypoglycemia.

Objectives: Create and evaluate the effectiveness of a structured education program in children and young people (CYP) with type 1 diabetes using continuous glucose monitoring (CGM).

Design And Methods: Step 1: CGM devices were evaluated for predetermined criteria using a composite score. Step 2: The education program was developed following review of international structured education guidance, dynamic glucose management (DynamicGM) literature, award-winning diabetes educators' websites, and CGM user feedback.

Causes, patterns and severity of androgen excess in 487 consecutively recruited pre- and post-pubertal children.

Objective Androgen excess in childhood is a common presentation and may signify sinister underlying pathology. Data describing its patterns and severity are scarce, limiting the information available for clinical decision processes. Here, we examined the differential diagnostic value of serum DHEAS, androstenedione (A4) and testosterone in childhood androgen excess.

Empowering youth sport environments: Implications for daily moderate-to-vigorous physical activity and adiposity.

Background: Evidence suggests involvement in youth sport does not guarantee daily guidelines for moderate-to-vigorous physical activity (MVPA) are met, and participation may not mitigate the risks associated with physical inactivity. The need to promote higher habitual MVPA engagement amongst children active in the youth sport context has therefore been underlined. Framed by self-determination theory, the aim of the present study was to examine the implications of the motivational climate created in youth sport, for children's daily engagement in MVPA and associated adiposity.

Treatment adherence and BMI reduction are key predictors of HbA1c 1 year after diagnosis of childhood type 2 diabetes in the United Kingdom.

Background/objective: Type 2 Diabetes (T2DM) is increasing in childhood especially among females and South-Asians. Our objective was to report outcomes from a national cohort of children and adolescents with T2DM 1 year following diagnosis.

Methods: Clinician reported, 1-year follow-up of a cohort of children (<17 years) diagnosed with T2DM reported through the British Paediatric Surveillance Unit (BPSU) (April 2015-April 2016).

Targets and teamwork: Understanding differences in pediatric diabetes centers treatment outcomes.

Objective: The reason for center differences in metabolic control of childhood diabetes is still unknown. We sought to determine to what extent the targets, expectations, and goals that diabetes care professionals have for their patients is a determinant of center differences in metabolic outcomes.

Research Design And Methods: Children, under the age of 11 with type 1 diabetes and their parents treated at the study centers participated.

Evaluation of human dermal fibroblasts directly reprogrammed to adipocyte-like cells as a metabolic disease model.

Adipose tissue is the primary tissue affected in most single gene forms of severe insulin resistance, and growing evidence has implicated it as a site at which many risk alleles for insulin resistance identified in population-wide studies might exert their effect. There is thus increasing need for human adipocyte models in which to interrogate the function of known and emerging genetic risk variants. However, primary adipocyte cultures, existing immortalised cell lines and stem-cell based models all have significant biological or practical limitations.

Refining genotype-phenotype correlation in Alström syndrome through study of primary human fibroblasts.

Background: Alström syndrome (AS), featuring retinal dystrophy, neuronal deafness, cardiomyopathy, metabolic syndrome, and diffuse fibrosis, is caused by biallelic mutations in the centrosomal protein ALMS1. Genotype-phenotype correlation has been suggested without assessment of ALMS1 expression.

Methods: ALMS1 expression (real-time PCR and immunocytochemistry) and cilia formation (immunocytochemistry) were assessed in fibroblasts from deeply phenotyped volunteers diagnosed with AS recruited from a dedicated AS Service.

Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia.

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.

Steroid Sulfatase Deficiency and Androgen Activation Before and After Puberty.

Context: Steroid sulfatase (STS) cleaves the sulfate moiety off steroid sulfates, including dehydroepiandrosterone (DHEA) sulfate (DHEAS), the inactive sulfate ester of the adrenal androgen precursor DHEA. Deficient DHEA sulfation, the opposite enzymatic reaction to that catalyzed by STS, results in androgen excess by increased conversion of DHEA to active androgens. STS deficiency (STSD) due to deletions or inactivating mutations in the X-linked STS gene manifests with ichthyosis, but androgen synthesis and metabolism in STSD have not been studied in detail yet.

A truncating TPO mutation (Y55X) in patients with hypothyroidism and total iodide organification defect.

Unlabelled: Absract Purpose: Mutations in the TPO gene have been reported to cause congenital hypothyroidism (CH), and our aim in this study was to determine the genetic basis of congenital hypothyroidism in two affected children coming from a consanguineous family.

Methods: Since CH is usually inherited in autosomal recessive manner in consanguineous/multi case-families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the candidate genes. First we investigated the potential genetic linkage of the family to any known CH locus using microsatellite markers and then screened for mutations in linked-gene by Sanger sequencing.

Sarco(endo)plasmic reticulum ATPase is a molecular partner of Wolfram syndrome 1 protein, which negatively regulates its expression.

Wolfram syndrome is an autosomal recessive disorder characterized by neurodegeneration and diabetes mellitus. The gene responsible for the syndrome (WFS1) encodes an endoplasmic reticulum (ER)-resident transmembrane protein that is involved in the regulation of the unfolded protein response (UPR), intracellular ion homeostasis, cyclic adenosine monophosphate production and regulation of insulin biosynthesis and secretion. In this study, single cell Ca(2+) imaging with fura-2 and direct measurements of free cytosolic ATP concentration ([ATP]CYT) with adenovirally expressed luciferase confirmed a reduced and delayed rise in cytosolic free Ca(2+) concentration ([Ca(2+)]CYT), and additionally, diminished [ATP]CYT rises in response to elevated glucose concentrations in WFS1-depleted MIN6 cells.

One Base Deletion (c.2422delT) in the TPO Gene Causes Severe Congenital Hypothyroidism.

Objective: Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and mutations in the TPO gene have been reported to cause CH. Our aim in this study was to determine the genetic basis of CH in two affected individuals coming from a consanguineous family.

Methods: Since CH is usually inherited in autosomal recessive manner in consanguineous/multi-case families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the candidate genes.

A nonsense thyrotropin receptor gene mutation (R609X) is associated with congenital hypothyroidism and heart defects.

Congenital hypothyroidism (CH), one of the most important preventable causes of mental retardation, is a clinical condition characterized by thyroid hormone deficiency in newborns. CH is most often caused by defects in thyroid development leading to thyroid dysgenesis. The thyroid-stimulating hormone receptor (TSHR) is the main known gene causing thyroid dysgenesis in consanguineous families with CH.

An essential splice site mutation (c.317+1G>A) in the TSHR gene leads to severe thyroid dysgenesis.

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and 2% of cases have familial origin. Our aim in this study was to determine the genetic alterations in two siblings with CH coming from a consanguineous family. Because CH is often inherited in autosomal recessive manner in consanguineous/multicase-families, we first performed genetic linkage studies to all known causative CH loci followed by conventional sequencing of the linked gene.

A deletion including exon 2 of the TSHR gene is associated with thyroid dysgenesis and severe congenital hypothyroidism.

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and 2% of cases have a familial origin. Our aim in this study was to determine the genetic alterations in two siblings with CH coming from a consanguineous family. As CH is often inherited in an autosomal recessive manner in consanguineous/multi case-families, we first performed genetic linkage studies to all known causative CH loci followed by conventional sequencing of the linked gene.

A truncating DUOX2 mutation (R434X) causes severe congenital hypothyroidism.

Mutations in DUOX2 have been reported to cause congenital hypothyroidism (CH), and our aim in this study was to determine the genetic basis of CH in two affected individuals coming from a consanguineous family. Because CH is usually inherited in autosomal recessive manner in consanguineous/multicase families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the candidate genes. First, we investigated the potential genetic linkage of the family to any known CH locus using microsatellite markers and then screened for mutations in linked genes by Sanger sequencing.

EURO-WABB: an EU rare diseases registry for Wolfram syndrome, Alström syndrome and Bardet-Biedl syndrome.

Background: Wolfram, Alström and Bardet-Biedl (WABB) syndromes are rare diseases with overlapping features of multiple sensory and metabolic impairments, including diabetes mellitus, which have caused diagnostic confusion. There are as yet no specific treatments available, little or no access to well characterized cohorts of patients, and limited information on the natural history of the diseases. We aim to establish a Europe-wide registry for these diseases to inform patient care and research.

Novel truncating thyroglobulin gene mutations associated with congenital hypothyroidism.

Mutations in the thyroglobulin (TG) gene have been reported to cause congenital hypothyroidism (CH) and we have been investigating the genetic architecture of CH in a large cohort of consanguineous/multi-case families. Our aim in this study was to determine the genetic basis of CH in four affected individuals coming from two separate consanguineous families. Since CH is usually inherited in autosomal recessive manner in consanguineous/multi-case families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the TG gene.