Congenital hypopituitarism (CH) is characterized by the deficiency of one or more pituitary hormones and can present alone or in association with complex disorders. Congenital hyperinsulinism (CHI) is a disorder of unregulated insulin secretion despite hypoglycaemia that can occur in isolation or as part of a wider syndrome. Molecular diagnosis is unknown in many cases of CH and CHI. The underlying genetic etiology causing the complex phenotype of CH and CHI is unknown. In this study, we identified a de novo heterozygous mutation in the developmental transcription factor, forkhead box A2, FOXA2 (c.505T>C, p.S169P) in a child with CHI and CH with craniofacial dysmorphic features, choroidal coloboma and endoderm-derived organ malformations in liver, lung and gastrointestinal tract by whole exome sequencing. The mutation is at a highly conserved residue within the DNA binding domain. We demonstrated strong expression of Foxa2 mRNA in the developing hypothalamus, pituitary, pancreas, lungs and oesophagus of mouse embryos using in situ hybridization. Expression profiling on human embryos by immunohistochemistry showed strong expression of hFOXA2 in the neural tube, third ventricle, diencephalon and pancreas. Transient transfection of HEK293T cells with Wt (Wild type) hFOXA2 or mutant hFOXA2 showed an impairment in transcriptional reporter activity by the mutant hFOXA2. Further analyses using western blot assays showed that the FOXA2 p.(S169P) variant is pathogenic resulting in lower expression levels when compared with Wt hFOXA2. Our results show, for the first time, the causative role of FOXA2 in a complex congenital syndrome with hypopituitarism, hyperinsulinism and endoderm-derived organ abnormalities.

Obesity is becoming increasingly prevalent in paediatric populations worldwide. In addition to increasing prevalence, the severity of obesity is also continuing to rise. Taken together, these findings demonstrate a worrying trend and highlight one of the most significant challenges to public health. Childhood obesity affects multiple organs in the body and is associated with both significant morbidity and ultimately premature mortality. The prevalence of complications associated with obesity, including dyslipidaemia, hypertension, fatty liver disease and psychosocial complications are becoming increasingly prevalent within the paediatric populations. Treatment guidelines currently focus on intervention with lifestyle and behavioural modifications, with pharmacotherapy and surgery reserved for patients who are refractory to such treatment. Research into adult obesity has established pharmacological novel therapies, which have been approved and established in clinical practice; however, the research and implementation of such therapies in paediatric populations have been lagging behind. Despite the relative lack of widespread research in comparison to the adult population, newer therapies are being trialled, which should allow a greater availability of treatment options for childhood obesity in the future. This review summarizes the current evidence for the management of obesity in terms of medical and surgical options. Both future therapeutic agents and those which cause weight loss but have an alternative indication are also included and discussed as part of the review. The review summarizes the most recent research for each intervention and demonstrates the potential efficacy and limitations of each treatment option.

The relationship between vitamin D deficiency and type I DM is an ongoing area of interest. The study aims to identify the prevalence of vitamin D deficiency in children and adolescents with T1DM and to assess the impact of treatment of vitamin D deficiency on their glycaemic control. Retrospective data was collected from 271 children and adolescents with T1DM. The vitamin D deficient (25(OH)D <30 nmol/L) and insufficient (25(OH)D 30–50 nmol/L) patients were treated with 6000 units of cholecalciferol and 400 units of cholecalciferol, once daily for 3 months respectively. HbA1c and 25(OH)D concentrations were measured before and at the end of the vitamin D treatment. 14.8% from the whole cohort (n = 271) were vitamin D deficient and 31% were insufficient. Among the children included in the final analysis (n = 73), the mean age and plasma 25(OH)D concentration (±SD) were 7.7 years (±4.4) and 32.2 nmol/l (±8.2) respectively. The mean 25(OH)D concentration post-treatment was 65.3 nmol/l (±9.3). The mean HbA1c (±SD) before and after cholecalciferol was 73.5 mmol/mol (±14.9) and 65 mmol/mol (±11.2) respectively (p < 0.001). Children with higher pre-treatment HbA1c had greater reduction in HbA1c (p < 0.001) and those with lower 25(OH)D concentration showed higher reduction in HbA1c (p = 0.004) after treatment. Low 25(OH)D concentrations are fairly prevalent in children and adolescents with T1DM, treatment of which, can potentially improve the glycaemic control.

Congenital hyperinsulinism (CHI) is a rare disease characterized by an unregulated insulin release, leading to hypoglycaemia. It is the most frequent cause of persistent and severe hypoglycaemia in the neonatal period and early childhood. Mutations in 16 different key genes ( ABCC8 , KCNJ11 , GLUD1 , GCK , HADH , SLC16A1 , UCP2 , HNF4A , HNF1A , HK1 , KCNQ1 , CACNA1D , FOXA2 , EIF2S3 , PGM1 and PMM2 ) that are involved in regulating the insulin secretion from pancreatic β-cells have been described to be responsible for the underlying molecular mechanisms of CHI. CHI can also be associated with specific syndromes and can be secondary to intrauterine growth restriction (IUGR), maternal diabetes, birth asphyxia, etc. It is important to diagnose and promptly initiate appropriate management as untreated hypoglycaemia can be associated with significant neurodisability. CHI can be histopathologically classified into diffuse, focal and atypical forms. Advances in molecular genetics, imaging techniques (18F-fluoro- l -dihydroxyphenylalanine positron emission tomography/computed tomography scanning), novel medical therapies and surgical advances (laparoscopic pancreatectomy) have changed the management and improved the outcome of patients with CHI. This review article provides an overview of the background, clinical presentation, diagnosis, molecular genetics and therapy for children with different forms of CHI.

Early diagnosis of girls with Turner syndrome (TS) is essential to provide timely intervention and support. The screening guidelines for TS suggest karyotype evaluation in patients presenting with short stature, webbed neck, lymphoedema, coarctation of aorta or ≥ two dysmorphic features. The aim of the study was to determine the age and clinical features at the time of presentation and to identify potential delays in diagnosis of TS. Retrospective data on age at diagnosis, reason for karyotype analysis and presenting clinical features was collected from the medical records of 67 girls with TS. The mean age of diagnosis was 5.89 (±5.3) years ranging from pre-natal to 17.9 years (median 4.6 years). 10% were diagnosed antenatally, 16% in infancy, 54% in childhood (1–12 years) and 20% in adolescence (12–18 years). Lymphoedema (27.3%) and dysmorphic features (27.3%) were the main signs that triggered screening in infancy. Short stature was the commonest presenting feature in both childhood (52.8%) and adolescent (38.5%) years. At least 12% of girls fulfilled the criteria for earlier screening but were diagnosed only at a later age (mean age = 8.78 years). 13.4% of patients had classical 45XO karyotype and 52.3% of girls had a variant karyotype. Majority of girls with TS were diagnosed only after the age of 5 years. Short stature triggered evaluation for most patients diagnosed in childhood and adolescence. Lack of dedicated community height-screening programme to identify children with short stature and lack of awareness could have led to potential delays in diagnosing TS. New strategies for earlier detection of TS are needed.

The factory calibrated FreeStyle Libre (FSL) flash glucose monitoring system has been recently introduced for use in patients with diabetes mellitus. There are no reports available regarding its use in patients with congenital hyperinsulinism (CHI). We have assessed the accuracy of FSL compared to the finger prick capillary blood glucose (CBG) over 2 weeks period in patients with CHI and evaluated the parents’ experience of using FSL. Four hundred sixty-seven episodes of CBG along with corresponding swipe FSL readings were available from 11 children with CHI (0.5–5 years). A detailed questionnaire was completed by the parents. The mean variation between the two methods was 0.29 mmol/l (SD ±1.07), higher readings by FSL compared to CBG. The FSL sensors stayed in-situ for an average period of 11.5 days. There was a positive correlation between the two methods (r = 0.7). The FSL tended to overestimate compared to CBG (bias = 0.29 mmol/l; 95% CI: 0.19 to 0.38). Only 70% of values were within the reference standard (±0.83 mmol/l) at glucose concentrations less than 5.6 mmol/l. The overall Mean Absolute Relative Difference (MARD) was 17.9%. Forty two episodes of hypoglycaemia (CBG < 3.5 mmol/l) were noted but FSL identified only 52% of these episodes. The Bland Altman analysis showed the 95% limits of agreement between the two methods ranging from − 1.8 (95% CI: -1.97 to − 1.64) to 2.37 (95% CI: 2.21 to 2.54). Majority of the parents found the glucose trend on FSL to be useful to detect and prevent hypoglycaemic episodes. All parents felt that FSL is a very easy and convenient method to measure the glucose especially during sleep. A significant proportion of parents felt that FSL readings were not accurate and 56% of parents expressed interest to continue using FSL after the trial period. Noticeable variability between the two methods of measuring the glucose was noted. Despite the ease of using the FSL system, concerns related to accuracy, especially at low glucose values do remain although parents find the glucose trend to be very useful. Further larger trials are needed in CHI patients before FSL is recommended as a routine alternative method for measuring glucose levels.