Novel compound heterozygous <i>ASXL3</i> mutation causing Bainbridge-ropers like syndrome and primary IGF1 deficiency.

BackgroundDe novo truncating and splicing mutations in the additional sex combs-like 3 (ASXL3) gene have been implicated in the development of Bainbridge-Ropers syndrome (BRPS) characterised by severe developmental delay, feeding problems, short stature and characteristic facial features.Case presentationWe describe, for the first time, a patient with severe short stature, learning difficulties, feeding difficulties and dysmorphic features with a novel compound heterozygous mutation in ASXL3.Additionally the patient also has primary insulin like growth factor-1 (IGF1) deficiency. The mutations occur in exon 11 and proximal part of exon 12 and are strongly conserved at the protein level across various species. In-silico analyses using PolyPhen-2 and SIFT predict the amino acid substitutions to be potentially deleterious to the protein function. Detailed bioinformatics analysis show that the molecular defects caused by the two compound heterozygous mutations synergistically impact on two points of the molecular interaction network of ASXL3.ConclusionWe hypothesise that ASXL3 potentially has a role in transcriptional activation of IGF1 involved in signalling pathways that regulate cell proliferation and growth, which could be contributing to short stature encountered in these patients

An eHealth Framework for Managing Pediatric Growth Disorders and Growth Hormone Therapy

Background: The use of technology to support health and health care has grown rapidly in the last decade across all ages and medical specialties. Newly developed eHealth tools are being implemented in long-term management of growth failure in children, a low prevalence pediatric endocrine disorder. Objective: Our objective was to create a framework that can guide future implementation and research on the use of eHealth tools to support patients with growth disorders who require growth hormone therapy. Methods: A total of 12 pediatric endocrinologists with experience in eHealth, from a wide geographical distribution, participated in a series of online discussions. We summarized the discussions of 3 workshops, conducted during 2020, on the use of eHealth in the management of growth disorders, which were structured to provide insights on existing challenges, opportunities, and solutions for the implementation of eHealth tools across the patient journey, from referral to the end of pediatric therapy. Results: A total of 815 responses were collected from 2 questionnaire-based activities covering referral and diagnosis of growth disorders, and subsequent growth hormone therapy stages of the patient pathway, relating to physicians, nurses, and patients, parents, or caregivers. We mapped the feedback from those discussions into a framework that we developed as a guide to integration of eHealth tools across the patient journey. Responses focused on improved clinical management, such as growth monitoring and automation of referral for early detection of growth disorders, which could trigger rapid evaluation and diagnosis. Patient support included the use of eHealth for enhanced patient and caregiver communication, better access to educational opportunities, and enhanced medical and psychological support during growth hormone therapy management. Given the potential availability of patient data from connected devices, artificial intelligence can be used to predict adherence and personalize patient support. Providing evidence to demonstrate the value and utility of eHealth tools will ensure that these tools are widely accepted, trusted, and used in clinical practice, but implementation issues (eg, adaptation to specific clinical settings) must be addressed. Conclusions: The use of eHealth in growth hormone therapy has major potential to improve the management of growth disorders along the patient journey. Combining objective clinical information and patient adherence data is vital in supporting decision-making and the development of new eHealth tools. Involvement of clinicians and patients in the process of integrating such technologies into clinical practice is essential for implementation and developing evidence that eHealth tools can provide value across the patient pathway.Peer reviewe

Using referral rates for genetic testing to determine the incidence of a rare disease: The minimal incidence of congenital hyperinsulinism in the UK is 1 in 28,389

This is the final version. Available from PLOS via the DOI in this record. Congenital hyperinsulinism (CHI) is a significant cause of hypoglycaemia in neonates and infants with the potential for permanent neurologic injury. Accurate calculations of the incidence of rare diseases such as CHI are important as they inform health care planning and can aid interpretation of genetic testing results when assessing the frequency of variants in large-scale, unselected sequencing databases. Whilst minimal incidence rates have been calculated for four European countries, the incidence of CHI in the UK is not known. In this study we have used referral rates to a central laboratory for genetic testing and annual birth rates from census data to calculate the minimal incidence of CHI within the UK from 2007 to 2016. CHI was diagnosed in 278 individuals based on inappropriately detectable insulin and/or C-peptide measurements at the time of hypoglycaemia which persisted beyond 6 months of age. From these data, we have calculated a minimum incidence of 1 in 28,389 live births for CHI in the UK. This is comparable to estimates from other outbred populations and provides an accurate estimate that will aid both health care provision and interpretation of genetic results, which will help advance our understanding of CHI.Wellcome Trus

Standardised practices in the networked management of congenital hyperinsulinism: a UK national collaborative consensus

Congenital hyperinsulinism (CHI) is a condition characterised by severe and recurrent hypoglycaemia in infants and young children caused by inappropriate insulin over-secretion. CHI is of heterogeneous aetiology with a significant genetic component and is often unresponsive to standard medical therapy options. The treatment of CHI can be multifaceted and complex, requiring multidisciplinary input. It is important to manage hypoglycaemia in CHI promptly as the risk of long-term neurodisability arising from neuroglycopaenia is high. The UK CHI consensus on the practice and management of CHI was developed to optimise and harmonise clinical management of patients in centres specialising in CHI as well as in non-specialist centres engaged in collaborative, networked models of care. Using current best practice and a consensus approach, it provides guidance and practical advice in the domains of diagnosis, clinical assessment and treatment to mitigate hypoglycaemia risk and improve long term outcomes for health and well-being

An Evaluation of Growth Hormone and IGF-1 Responses in Neonates with Hyperinsulinaemic Hypoglycaemia

Background. Hyperinsulinaemic Hypoglycaemia (HH) is the most common cause of severe and persistent hypoglycemia in the neonatal period. It has been shown that the neonates with HH fail to generate adequate serum cortisol counterregulatory response to symptomatic hypoglycemia. However the role played by growth hormone (GH) and Insulin-like Growth Factor 1 (IGF-1) is not clear. Objectives. To compare the serum GH, IGF-1, and IGFBP3 responses to HH in neonates undergoing diagnostic fasting studies. Population and Methods. Data was retrospectively collected on full-term neonates who presented with severe and persistent hypoglycemia and were confirmed to have HH. Neonates born with intrauterine growth retardation or those on medical therapy (diazoxide or octreotide) were excluded. Results. 31 neonates with HH (mean gestational age: 38 weeks and mean birth weight: 3.9 kg) were included in the study. The mean age at the time of diagnostic fast was 4 weeks, the mean glucose concentration during the fast was 2.2 mmol/L (), and the mean insulin level was 11.9 mU/L (±2.12). The mean serum GH concentration during the hypoglycaemia was 12.5 µg/L (±1.53). The mean serum IGF-1 and Insulin-like Growth Factor Binding Protein 3 (IGFBP3) levels were 29.2 ng/ml (±7.8) and 1.21 mg/L (±0.13), respectively. The mean cortisol concentration was 201 nmol/L (±33). Conclusions. Whilst the serum IGF-1 and IGFBP3 levels are relatively low during hypoglycaemia, the serum GH level does reflect an appropriate counterregulatory response to HH. The serum cortisol counterregulatory hormonal responses are blunted. Further studies are required to understand the mechanism(s) of these hormonal alterations in neonates with HH

A rare association of central hypothyroidism and adrenal insufficiency in a boy with Williams-Beuren syndrome

Primary hypothyroidism related to morphological and volumetric abnormalities of the thyroid gland is one of the commonest of several endocrine dysfunctions in Williams-Beuren syndrome (WBS). We report a 10-month-old boy with WBS who presented with central hypothyroidism. During the neonatal period, he had prolonged jaundice, feeding difficulties and episodes of colic that continued during early infancy. Additionally, there was slowing of growth and mild developmental delay. He underwent surgical repair for supravalvular aortic stenosis at 6 months of age. An evaluation done to exclude cortisol deficiency before initiating levothyroxine lead to the detection of secondary adrenal insufficiency, unreported previously in WBS. In addition, insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 levels were low. This report of hypopituitarism in WBS indicates a need for complete evaluation of pituitary dysfunction in children with WBS

The molecular mechanisms, diagnosis and management of congenital hyperinsulinism

Congenital hyperinsulinism (CHI) is the result of unregulated insulin secretion from the pancreatic β-cells leading to severe hypoglycaemia. In these patients it is important to make an accurate diagnosis and initiate the appropriate management so as to avoid hypoglycemic episodes and prevent the potentially associated complications like epilepsy, neurological impairment and cerebral palsy. At a genetic level abnormalities in eight different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and UCP2) have been reported with CHI. Loss of function mutations in ABCC8/KCNJ11 lead to the most severe forms of CHI which are usually medically unresponsive. At a histological level there are two major subgroups, diffuse and focal, each with a different genetic etiology. The focal form is sporadic in inheritance and is localized to a small region of the pancreas whereas the diffuse form is inherited in an autosomal recessive (or dominant) manner. Imaging using a specialized positron emission tomography scan with the isotope fluroine-18 L-3, 4-dihydroxyphenyalanine (18F-DOPA-PET-CT) is used to accurately locate the focal lesion pre-operatively and if removed can cure the patient from hypoglycemia. Understanding the molecular mechanisms, the histological basis, improvements in imaging modalities and surgical techniques have all improved the management of patients with CHI

Novel Splicing Mutation in B3GAT3 Associated with Short Stature, GH Deficiency, Hypoglycaemia, Developmental Delay, and Multiple Congenital Anomalies

B3GAT3, encoding β-1,3-glucuronyltransferase 3, has an important role in proteoglycan biosynthesis. Homozygous B3GAT3 mutations have been associated with short stature, skeletal deformities, and congenital heart defects. We describe for the first time a novel heterozygous splice site mutation in B3GAT3 contributing to severe short stature, growth hormone (GH) deficiency, recurrent ketotic hypoglycaemia, facial dysmorphism, and congenital heart defects. A female infant, born at 34 weeks’ gestation to nonconsanguineous Caucasian parents with a birth weight of 1.9 kg, was noted to have cloacal abnormality, ventricular septal defect, pulmonary stenosis, and congenital sensorineural deafness. At 4 years of age, she was diagnosed with GH deficiency due to her short stature (height G) in the invariant “GT” splice donor site was identified. This variant is considered to be pathogenic as it decreases the splicing efficiency in the mRNA