Paediatric survivors beyond infancy with Stüve-Wiedemann syndrome - A case series from the West Midlands, UK.

Stüve-Wiedemann Syndrome (STWS) is an autosomal recessive condition caused by variants in the LIFR gene, presenting with respiratory failure, hyperthermia and skeletal dysplasia in the neonatal period. Historically identified as a lethal condition, more children are now managed holistically from early in life with multidisciplinary team involvement with improved outcomes. This stems from early diagnosis, supported by molecular testing in the pre and postnatal periods. This report includes five such cases with survival in childhood to 10 years old in the UK affected by skeletal abnormalities, hyperthermia, respiratory distress and their diagnostic odyssey. All cases have a molecular diagnosis; two patients (family 1) were found to be homozygous for a novel pathogenic LIFR variant NM_002310.5:c.704G > A, p.(Trp235Ter). One patient (family 2) is compound heterozygous with the previously reported LIFR variant NM_002310.5:c.756dup p.(Lys253Ter), and a second novel variant NM_002310.5:c.397+5G > A. Two patients (family 3) are homozygous for one of the same LIFR variants NM_002310.5:c.756dup p.(Lys253Ter) as in family 2. This report discusses genotypic and phenotypic data for five patients with STWS, as well as the need for multi-disciplinary, proactive management and genetic counselling.

Rapid exome sequencing in critically ill children impacts acute and long-term management of patients and their families: A retrospective regional evaluation.

INTRODUCTION: Genetic disorders are a significant cause of paediatric morbidity and mortality. Rapid exome sequencing was introduced by the National Health Service (NHS) in England on 1st October 2019 for acutely unwell children with a likely monogenic disorder, or to inform current pregnancy management where there was a previously affected child or fetus. We present results of a 12-month patient cohort from one large clinical genetics centre in England. METHODS: Patients were identified through local genetics laboratory records. We included all cases which underwent rapid exome sequencing between 1st October 2020 and 30th September 2021. DNA was extracted, quality checked and exported to the Exeter Genomic laboratory where library preparation, exome sequencing of all known human genes, gene-agnostic bioinformatic analysis, variant interpretation, MDT discussions and reporting were performed. RESULTS: Ninety-five probands were included. Trio analysis was performed in 90% (85), duo in 8% (8), singleton in 2% (2). The median turnaround time for preliminary reports was 11 days. The overall diagnostic yield was 40% (38 patients); 36% (34 patients) made solely on exome with a further 4% on concomitant exome and microarray analysis. Highest diagnostic rates were seen in patients with neuro-regression, skeletal dysplasia, neuromuscular and neurometabolic conditions. Where the diagnosis was made solely through exome sequencing, management was altered for the proband or family in 97% (33/34). For the proband, this was most commonly that the diagnosis was able to inform current management and prognosis (20 patients, 59%), as well as direct specialist referrals (10 patients, 29%). For families, the exome sequencing results provided accurate recurrence risk counselling in 88% (30/34) with cascade testing offered if indicated in some families. CONCLUSIONS: In the majority of cases, the genetic diagnoses influenced acute and long-term management for critically ill children and their families. Paediatric and neonatal clinicians in the NHS now have direct access to exome sequencing for their patients. The rapid turnaround time was particularly helpful to alter the management in acute clinical settings and is a powerful tool for diagnosing monogenic conditions. This study is an example of a highly successful integration of a national rapid exome sequencing service with diagnostic rates comparable to previously reported literature.

Implementing less invasive surfactant administration on a neonatal unit.

There is increasing evidence reflected in both UK 2019 NICE and European guidelines suggesting that less invasive surfactant administration (LISA) reduces the need for mechanical ventilation and reduces the combined outcome of death or bronchopulmonary dysplasia, and is now the optimal method for surfactant delivery in spontaneously breathing babies. Despite this, uptake in England has been slow compared with Europe. This quality improvement project outlines the process of implementing LISA in a neonatal intensive care unit over a 2-year period, the barriers and challenges which were encountered, and how they were overcome.

Robinow syndrome in an extremely preterm infant: Novel homozygous ROR2 variant detected by rapid exome sequencing.

An extremely preterm infant presented with clinical and radiological features of Robinow syndrome including butterfly vertebrae, posterior rib fusion, brachydactyly, nail hypoplasia, and retromicrognathia resulting in difficult endotracheal intubation in the intensive care setting. Rapid trio exome sequencing detected a novel homozygous likely pathogenic missense variant in the ROR2 gene, NM_004560.3:c.950A>G, p.(Tyr317Cys), for which both parents were heterozygous carriers. In-silico protein modeling predicted a deleterious effect on the function of the protein. We report an extreme premature infant with novel homozygous likely pathogenic variant in the ROR2 gene consistent with autosomal recessive Robinow syndrome. This case expands the phenotypic and genotypic spectrum of this disorder and highlights the benefit of performing rapid exome sequencing early during evaluation to aid in patient management and providing accurate genetic counseling to families.

Novel compound heterozygous TTN variants as a cause of severe neonatal congenital contracture syndrome without cardiac involvement diagnosed with rapid trio exome sequencing.

This report focuses on a case of severe congenital myopathy with arthrogryposis without cardiac involvement due to compound heterozygous variants in the TTN gene. The proband presented with severe axial hypotonia, arthrogryposis and severe respiratory insufficiency with ventilator dependence. Electromyogram was abnormal with absent motor responses but preserved sensory nerve responses. Rapid gene-agnostic trio exome sequencing detected novel compound heterozygous variants in the TTN gene. One variant is a truncating frameshift located in the meta-transcript only exon 195. The other variant is a nonsense variant in exon 327 which affects all recognised post-natal transcripts apart from one. This case presents with a severe phenotype and adds to the expanding known variants associated with autosomal recessive titinopathy. It also demonstrates the utility of rapid trio exome sequencing when used early in the clinical course.

Home phototherapy for neonatal jaundice in the UK: a single-centre retrospective service evaluation and parental survey.

Background: In the UK setting, where neonatal jaundice treatment is required, it is largely carried out in hospitals. However, it is possible to safely administer home phototherapy (HPT). Objective: To report on our centre's experience of HPT and its potential benefits. Design: Retrospective observational study performed as a service evaluation. Patients: Infants ≥35 weeks corrected gestational age with a weight of 2 kg and serum bilirubin ≤50 µmol/L above treatment thresholds. Controls were a matched group of infants who received inpatient phototherapy (IPT). Setting: The catchment area of two neonatal intensive care units, one special care unit and a birth centre at four different hospitals that is covered by a single neonatal community outreach nursing team in Birmingham, UK. Intervention: HPT was started either in the community or as a continuation of IPT. Controls received IPT. Main outcome measures: The rate of bilirubin reduction, hospital readmission rates and parental satisfaction. Results: 100 infants received HPT while 50 received IPT. No infant showed a progressive rise of serum bilirubin level while receiving HPT. The rate of bilirubin reduction was similar in both HPT and IPT groups (2.4±1.9 and 2.5±1.6 µmol/L/hour, respectively, MD=-0.1, 95% CI -0.74 to 0.53, p=0.74). Readmission rate was 3% in the HPT group. 97% of parents stated that the overall experience was good and 98% would choose HPT if they had their time all over again. Conclusion: Our programme suggests that HPT for neonatal jaundice can be carried out in a select group of infants. It helps in providing holistic family-centred care and is viewed positively by families.

Rare case of pseudohypoaldosteronism in a neonate secondary to congenital hydrometrocolpos.

Pseudohypoaldosteronism (PHA) due to obstructive uropathy, urinary tract infections and congenital urogenital malformations has been reported in the literature; however, there are no reports of PHA associated with hydrometrocolpos due to a common urogenital tract. Hydrometrocolpos is a condition resulting in distension of the vagina and uterus due to accumulation of secretions (other than blood), caused by increased oestrogenic stimulation and vaginal outflow obstruction. We report on a neonatal case of PHA caused by recurrent hydrometrocolpos presenting with vomiting and poor weight gain. There was significant hyponatraemia, hyperkalaemia, and anaemia requiring medical stabilisation prior to surgery. The mechanism by which PHA occurs in obstruction involves renal tubular dysfunction due to pressure from hydronephrosis and the release of intrarenal cytokines. In addition, there is an immature or resistant renal tubular responsiveness to aldosterone during infancy. Clinicians should be aware of this uncommon but serious presentation.

UK trainee-led paediatric governance collaboratives: improving the lives of both trainees and children.

Research is vital to paediatrics; however, many trainees feel there is a deficit in their opportunities, experience and exposure in this area. Three training regions in the UK, the West Midlands, Wales and Peninsula, have recently started region-wide, trainee-led research and governance collaboratives aimed at improving trainee access and education in research, undertaking good quality, multicentre audit, quality improvement and pilot projects in collaboration across the regions and implementing change. We report on the experiences, benefits and challenges of these trainee collaboratives (Paediatric Research Across the Midlands, Wales Research and Education Network and Peninsula Trainee Research Audit and Innovation Network) including a trainee survey looking at how these initiatives have improved skills in conducting multicentre prospective studies, team working skills, leadership, understanding of statistics and manuscripts and presentation skills. We also describe how collaboration with colleagues and participation in projects can benefit trainees in a wider sense of purpose and help to encourage morale, as well as what can be learnt as paediatric training moves forward.

A comparison of course-related stressors in undergraduate problem-based learning (PBL) versus non-PBL medical programmes.

BACKGROUND: Medical students report high levels of stress related to their medical training as well as to other personal and financial factors. The aim of this study is to investigate whether there are differences in course-related stressors reported by medical students on undergraduate problem-based learning (PBL) and non-PBL programmes in the UK. METHOD: A cross-sectional study of second-year medical students in two UK medical schools (one PBL and one non-PBL programme) was conducted. A 16-question self-report questionnaire, derived from the Perceived Medical Student Stress Scale and the Higher Education Stress Inventory, was used to measure course-related stressors. Following univariate analysis of each stressor between groups, multivariate logistic regression was used to determine which stressors were the best predictors of each course type, while controlling for socio-demographic differences between the groups. RESULTS: A total of 280 students responded. Compared to the non-PBL students (N = 197), the PBL students (N = 83) were significantly more likely to agree that: they did not know what the faculty expected of them (Odds Ratio (OR) = 0.38, p = 0.03); there were too many small group sessions facilitated only by students resulting in an unclear curriculum (OR = 0.04, p < 0.0001); and that there was a lack of opportunity to explore academic subjects of interest (OR = 0.40, p = 0.02). They were significantly more likely to disagree that: there was a lack of encouragement from teachers (OR = 3.11, p = 0.02); and that the medical course fostered a sense of anonymity and feelings of isolation amongst students (OR = 3.42, p = 0.008). CONCLUSION: There are significant differences in the perceived course-related stressors affecting medical students on PBL and non-PBL programmes. Course designers and student support services should therefore tailor their work to minimise, or help students cope with, the specific stressors on each course type to ensure optimum learning and wellbeing among our future doctors.

A case report of pulmonary alveolar proteinosis.

This is a case of pulmonary alveolar proteinosis that presented in an inner city hospital in Birmingham, UK. The patient was a previously well 42-year-old man, who went on to experience unusual cerebral complications of the disease. The presentation, imaging findings and diagnostic histology findings are described. Pulmonary alveolar proteinosis is a rare but important diagnosis. Characteristic high-resolution CT findings include diffuse ground glass density with superimposed interlobular septal thickening, which is described as the "crazy paving" pattern. Diagnosis is made by bronchoalveolar lavage. Pathologically the disease is characterised by alveolar filling with a lipid rich, proteinaceous material (positive to periodic acid-Schiff stain) while the lung interstitium remains relatively normal. Morbidity and mortality can be improved by treatment with whole lung lavage.