Neonatal features of the Prader-Willi syndrome; the case for making the diagnosis during the first week of life

Early diagnosis is of proven benefit in Prader-Willi syndrome (PWS). We therefore examined key perinatal features to aid early recognition. Data were collected from case records of subjects attending a multi-disciplinary clinic and from a retrospective birth questionnaire. Ninety patients (54 male: 36 female) were seen between 1991-2015, most with paternal deletion (n=56) or maternal isodisomy (n=26). Features included cryptorchidism in 94% males, preterm birth (26%), birthweight <2500g (24%), polyhydramnios (23%), breech presentation (23%) and need for nasogastric feeding (83%). Reduced fetal movements (FM) occurred in 82.5% patients compared with 4% healthy siblings. Of 35 children born since 1999, 23 were diagnosed clinically within 28 days while diagnosis in 12 was > 28 days: 1-12 months in 7; and 3.75-10.5 years in 5. Typical PWS features in these 12 infants included hypotonia (100%), feeding difficulties (75%), cryptorchidism (83% males) and reduced FM (66%). Causes other than PWS including neuromuscular disease were considered in nine patients. Neonatal hypotonia, reduced FM, feeding difficulties and cryptorchidism should immediately suggest PWS, yet late diagnosis continues in some cases. Awareness of the typical features of PWS in newborn units is required to allow prompt detection even in the presence of confounding factors such as prematurity

Parent-reported outcomes in young children with disorders/differences of sex development

Background: There is a paucity of tools that can be used in routine clinical practice to assess the psychosocial impact of Disorders/Differences of Sex Development (DSD) on parents and children. Objective: To evaluate the use of short Parent Self-Report and Parent Proxy-Report questionnaires that can be used in the outpatient setting. Methods: Previously validated DSD-specific and generic items were combined to develop a Parent Self-Report questionnaire and a Parent Proxy-Report questionnaire for children under 7 years. Of 111 children approached at one tertiary paediatric hospital, the parents of 95 children (86%) with DSD or other Endocrine conditions completed these questionnaires. Results: Questionnaires took under 10 min to complete and were found to be easy to understand. Compared to reference, fathers of children with DSD reported less stress associated with Clinic Visits (p = 0.02) and managing their child’s Medication (p = 0.04). However, parents of children with either DSD or other Endocrine conditions reported more symptoms of Depression (p = 0.03). Mothers of children with DSD reported greater Future Concerns in relation to their child’s condition (median SDS − 0.28; range − 2.14, 1.73) than mothers of children with other Endocrine conditions (SDS 1.17; − 2.00, 1.73) (p = 0.02). Similarly, fathers of children with DSD expressed greater Future Concerns (median SDS -1.60; − 4.21, 1.00) than fathers of children with other Endocrine conditions (SDS 0.48; − 2.13, 1.52) (p = 0.04). Conclusion: DSD was associated with greater parental concerns over the child’s future than other Endocrine conditions. Brief parent-report tools in DSD can be routinely used in the outpatient setting to assess and monitor parent and patient needs

The effect of COVID-19 on the presentation of thyroid disease in children

Introduction: Although studies suggest a potential link between COVID-19 and thyroid dysfunction in adults, there are insufficient data to confirm that association in children, and whether there is any effect on presentation to healthcare services. Aims: To identify whether presentations of thyroid dysfunction in children to a tertiary paediatric hospital changed as a result of the COVID-19 pandemic. Methods: A retrospective case note review was conducted of all children with abnormal thyroid function tests between 1st January 2016 and 31st December 2021 at a tertiary paediatric endocrine centre in the United Kingdom. Results: Overall, 244 children whose first presentation was within the timeframe of interest were included in this study, with a median age (range) of 11.5 (6.1, 16.8) years. Of these, 43 (18%) were hyperthyroid and 201 (82%) were hypothyroid. The greatest number of thyroid presentations occurred in 2021 (n=60, 25% of total over time period) and the fewest in 2020 (n=10, 4% of total over time period). Prior to this, the median (range) number of presentations per year was 34 (28, 39). There were no statistically significant differences in biochemistry, antibody status or other clinical characteristics between those who presented with hyperthyroidism prior to the pandemic or after. In those with hypothyroidism, baseline biochemistry was similar between the 2 groups, but the presence of other autoimmune conditions was greater pre-pandemic (17.2% vs 15.0%, p=0.03). In addition, patients were more likely to have transient thyroid dysfunction, which did not require treatment post-pandemic (70.0% vs 49.6%, p=0.0086). Conclusions: Although overall rates of presentation with thyroid dysfunction have not altered since the first wave of the COVID-19 pandemic, presentations with transient thyroid dysfunction, not requiring ongoing treatment have increased. Further research regarding the relationship between COVID-19 and thyroid function in children and young people, is needed

DICER1 syndrome and its various paediatric presentations: case series and review of the literature

DICER1 syndrome is a rare tumour predisposition syndrome, associated with a range of benign and malignant tumours, which may occur during childhood. A high index of suspicion is required to ensure appropriate diagnosis and testing, with early treatment and surveillance of at-risk individuals. In this report, we present 5 patients with variants in DICER1 identified following diagnosis of a minimally invasive thyroid follicular cell carcinoma, a pineoblastoma, a pleuropulmonary blastoma, a urethral rhabdomyosarcoma and on sibling testing. Each of these children have presented at a young age, and 2 have presented with characteristic tumours prior to the ages currently recommended for initiation of routine screening. We discuss their presentation, management and follow up, as well as a review of the current literature on each associated tumour in relation to our patients. Overall, we demonstrate that DICER1 is a heterogenous condition and that there is a need for cascade testing of family members as well as regular screening for tumour development in affected children, although consideration should be made regarding initiating this screening at an earlier age depending on clinical findings

Management of cardiac aspects in children with Noonan syndrome – results from a European clinical practice survey among paediatric cardiologists

Background: The majority of children with Noonan syndrome (NS) or other diseases from the RASopathy spectrum suffer from congenital heart disease. This study aims to survey cardiac care of this patient cohort within Europe. Methods: A cross-sectional exploratory survey assessing the treatment and management of patients with NS by paediatric endocrinologists, cardiologists and clinical geneticists was developed. This report details responses of 110 participating paediatric cardiologists from multiple countries. Results: Most paediatric cardiologists responding to the questionnaire were associated with university hospitals, and most treated <10 patients/year with congenital heart disease associated with the NS spectrum. Molecular genetic testing for diagnosis confirmation was initiated by 81%. Half of the respondents reported that patients with NS and congenital heart disease typically present <1y of age, and that a large percentage of affected patients require interventions and pharmacotherapy early in life. A higher proportion of infant presentation and need for pharmacotherapy was reported by respondents from Germany and Sweden than from France and Spain (p = 0.031; p = 0.014; Fisher's exact test). Older age at first presentation was reported more from general hospitals and independent practices than from university hospitals (p = 0.031). The majority of NS patients were followed at specialist centres, but only 37% reported that their institution offered dedicated transition clinic to adult services. Very few NS patients with hypertrophic cardiomyopathy (HCM) were reported to carry implantable cardioverter defibrillators for sudden cardiac death prevention. Uncertainty was evident in regard to growth hormone treatment in patients with NS and co-existing HCM, where 13% considered it not a contra-indication, 24% stated they did not know, but 63% considered HCM either a possible (20%) or definite (15%) contraindication, or a cause for frequent monitoring (28%). Regarding adverse reactions for patients with NS on growth hormone therapy, 5/19 paediatric cardiology respondents reported a total of 12 adverse cardiac events. Conclusions: Congenital heart disease in patients with NS or other RASopathies is associated with significant morbidity during early life, and specialty centre care is appropriate. More research is needed regarding the use of growth hormone in patients with NS with congenital heart disease, and unmet medical needs have been identified

European Medical Education Initiative on Noonan Syndrome: A clinical practice survey assessing the diagnosis and clinical management of individuals with Noonan syndrome across Europe

Introduction: Noonan syndrome (NS) is a rare genetic disorder caused by mutations in genes encoding components of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway. Patients with NS exhibit certain characteristic features, including cardiac defects, short stature, distinctive facial appearance, skeletal abnormalities, cognitive deficits, and predisposition to certain cancers. Here, a clinical practice survey was developed to learn more about differences in the diagnosis and management of this disease across Europe. The aim was to identify gaps in the knowledge and management of this rare disorder. Materials and methods: The European Medical Education Initiative on NS, which comprised a group of 10 experts, developed a 60-question clinical practice survey to gather information from European physicians on the diagnosis and clinical management of patients with diseases in the NS phenotypic spectrum. Physicians from three specialities (clinical genetics, paediatric endocrinology, paediatric cardiology) were invited to complete the survey by several national and European societies. Differences in answers provided by respondents between specialities and countries were analysed using contingency tables and the Chi-Squared test for independence. The Friedman's test was used for related samples. Results: Data were analysed from 364 respondents from 20 European countries. Most respondents came from France (21%), Spain (18%), Germany (16%), Italy (15%), United Kingdom (8%) and the Czech Republic (6%). Respondents were distributed evenly across three specialities: clinical genetics (30%), paediatric endocrinology (40%) and paediatric cardiology (30%). Care practices were generally aligned across the countries participating in the survey. Delayed diagnosis did not emerge as a critical issue, but certain unmet needs were identified, including transition of young patients to adult medical services and awareness of family support groups. Conclusion: Data collected from this survey provide a comprehensive summary of the diagnosis and clinical management practices for patients with NS across different European countries

Application of a gene modular approach for clinical phenotype genotype association and sepsis prediction using machine learning in meningococcal sepsis

Sepsis is a major global health concern causing high morbidity and mortality rates. Our study utilized a Meningococcal Septic Shock (MSS) temporal dataset to investigate the correlation between gene expression (GE) changes and clinical features. The research used Weighted Gene Co-expression Network Analysis (WGCNA) to establish links between gene expression and clinical parameters in infants admitted to the Pediatric Critical Care Unit with MSS. Additionally, various machine learning (ML) algorithms, including Support Vector Machine (SVM), Naive Bayes, K-Nearest Neighbors (KNN), Decision Tree, Random Forest, and Artificial Neural Network (ANN) were implemented to predict sepsis survival. The findings revealed a transition in gene function pathways from nuclear to cytoplasmic to extracellular, corresponding with Pediatric Logistic Organ Dysfunction score (PELOD) readings at 0, 24, and 48 h. ANN was the most accurate of the six ML models applied for survival prediction. This study successfully correlated PELOD with transcriptomic data, mapping enriched GE modules in acute sepsis. By integrating network analysis methods to identify key gene modules and using machine learning for sepsis prognosis, this study offers valuable insights for precision-based treatment strategies in future research. The observed temporal-spatial pattern of cellular recovery in sepsis could prove useful in guiding clinical management and therapeutic interventions

Diazoxide choline extended‐release tablet in people with Prader‐Willi syndrome: results from long‐term open‐label study

Objective: This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi syndrome (PWS). Methods: The authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open-label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety. Results: DCCR administration resulted in significant improvements in HQ-CT (mean [SE] −9.9 [0.77], p < 0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ-CT > 22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment-emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%). Conclusions: DCCR administration to people with PWS was well tolerated and associated with broad-ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families

Advancing sepsis clinical research: harnessing transcriptomics for an omics-based strategy - a comprehensive scoping review

Sepsis continues to be recognized as a significant global health challenge across all ages and is characterized by a complex pathophysiology. In this scoping review, PRISMA-ScR guidelines were adhered to, and a transcriptomic methodology was adopted, with the protocol registered on the Open Science Framework. We hypothesized that gene expression analysis could provide a foundation for establishing a clinical research framework for sepsis. A comprehensive search of the PubMed database was conducted with a particular focus on original research and systematic reviews of transcriptomic sepsis studies published between 2012 and 2022. Both coding and non-coding gene expression studies have been included in this review. An effort was made to enhance the understanding of sepsis at the mRNA gene expression level by applying a systems biology approach through transcriptomic analysis. Seven crucial components related to sepsis research were addressed in this study: endotyping (n = 64), biomarker (n = 409), definition (n = 0), diagnosis (n = 1098), progression (n = 124), severity (n = 451), and benchmark (n = 62). These components were classified into two groups, with one focusing on Biomarkers and Endotypes and the other oriented towards clinical aspects. Our review of the selected studies revealed a compelling association between gene transcripts and clinical sepsis, reinforcing the proposed research framework. Nevertheless, challenges have arisen from the lack of consensus in the sepsis terminology employed in research studies and the absence of a comprehensive definition of sepsis. There is a gap in the alignment between the notion of sepsis as a clinical phenomenon and that of laboratory indicators. It is potentially responsible for the variable number of patients within each category. Ideally, future studies should incorporate a transcriptomic perspective. The integration of transcriptomic data with clinical endpoints holds significant potential for advancing sepsis research, facilitating a consensus-driven approach, and enabling the precision management of sepsis

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