Declan Cody

Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations

Objective The phenotype associated with heterozygous HNF4A gene mutations has recently been extended to include diazoxide responsive neonatal hypoglycemia in addition to maturity-onset diabetes of the young (MODY). To date, mutation screening has been limited to patients with a family history consistent with MODY. In this study, we investigated the prevalence of HNF4A mutations in a large cohort of patients with diazoxide responsive hyperinsulinemic hypoglycemia (HH). Subjects and methods We sequenced the ABCC8, KCNJ11, GCK, GLUD1, and/or HNF4A genes in 220 patients with HH responsive to diazoxide. The order of genetic testing was dependent upon the clinical phenotype. Results A genetic diagnosis was possible for 59/220 (27%) patients. KATP channel mutations were most common (15%) followed by GLUD1 mutations causing hyperinsulinism with hyperammonemia (5.9%), and HNF4A mutations (5%). Seven of the 11 probands with a heterozygous HNF4A mutation did not have a parent affected with diabetes, and four de novo mutations were confirmed. These patients were diagnosed with HI within the first week of life (median age 1 day), and they had increased birth weight (median +2.4 SDS). The duration of diazoxide treatment ranged from 3 months to ongoing at 8 years. Conclusions In this large series, HNF4A mutations are the third most common cause of diazoxide responsive HH. We recommend that HNF4A sequencing is considered in all patients with diazoxide responsive HH diagnosed in the first week of life irrespective of a family history of diabetes, once KATP channel mutations have been excluded.

Altered Distribution and Increased IL-17 Production by Mucosal-Associated Invariant T Cells in Adult and Childhood Obesity

Mucosal-associated invariant T (MAIT) cells are innate MHC-unrestricted cells that regulate inflammatory responses through the rapid production of cytokines. In this article, we show that circulating MAIT cells are depleted in obese adults, and depletion is associated with diabetic status. Circulating MAIT cells more frequently produced IL-17 upon stimulation ex vivo, a cytokine implicated in insulin resistance. MAIT cells were enriched in adipose tissue (AT) compared with blood. AT MAIT cells, but not circulating MAIT cells, were capable of producing IL-10. In AT from obese subjects, MAIT cells were depleted, were less likely to produce IL-10, and more frequently produced IL-17. Finally, we show that IL-17+ MAIT cells are also increased in childhood obesity, and altered MAIT cell frequencies in obese children are positively associated with insulin resistance. These data indicate that MAIT cells are enriched in human AT and display an IL-17+ phenotype in both obese adults and children, correlating with levels of insulin resistance. The alterations in MAIT cells may be contributing to obesity-related sterile inflammation and insulin resistance.

The Impact of Childhood Obesity on Inflammation, Innate Immune Cell Frequency, and Metabolic MicroRNA Expression

BACKGROUND Obesity is characterized by chronic inflammation, immune dysregulation, and alteration of gene expression, associated with type 2 diabetes mellitus and cardiovascular disease. The degree to which these changes occur in childhood obesity is not fully defined. AIMS AND METHODS The aim was to investigate the effect of childhood obesity on immune cell frequency, macrophage activation, cytokine production, and specific regulators of metabolic gene expression. Profiling was performed on peripheral blood from 29 obese and 20 nonobese children using real-time PCR, ELISA, and flow cytometry. RESULTS Fasting glucose was similar in both groups, but there was a higher degree of insulin resistance in obese subjects (homeostasis model of assessment for insulin resistance, 4.8 vs 0.84; P < .001). Soluble CD163, a marker of macrophage polarization to a proinflammatory profile, was elevated in the obese compared to nonobese children (135 vs 105 ng/mL; P = .03). Invariant natural killer T cells were reduced in the obese children (CD3 T cells, 0.31 vs 0.53%; P = .001). Cytokine profiling revealed significantly elevated TNF-α (6.7 vs 5.1 pg/mL; P = .01) and leptin (1186 vs 432 pg/mL; P < .001) and reduced adiponectin (884 vs 1321 pg/mL; P = .001) in obese compared to nonobese children. Stimulation of peripheral blood mononuclear cells from obese children resulted in higher levels of IL-1β (2100 vs 1500 pg/mL; P = .018). There was a 4-fold increase in expression of microRNA33a (P = .001) and a 3-fold increase in microRNA33b (P = .017) in obese children. CONCLUSION Childhood obesity is associated with changes in immune cell frequency, inflammatory environment, and regulation of metabolic gene expression. These changes have been causally linked to the onset of metabolic disease in adulthood and suggest the future trajectory of obese children to the development of type 2 diabetes mellitus and premature cardiovascular disease.

Unexpected Widespread Hypophosphatemia and Bone Disease Associated with Elemental Formula Use in Infants and Children

OBJECTIVE Hypophosphatemia occurs with inadequate dietary intake, malabsorption, increased renal excretion, or shifts between intracellular and extracellular compartments. We noticed the common finding of amino-acid based elemental formula [EF] use in an unexpected number of cases of idiopathic hypophosphatemia occurring in infants and children evaluated for skeletal disease. We aimed to fully characterize the clinical profiles in these cases. METHODS A retrospective chart review of children with unexplained hypophosphatemia was performed as cases accumulated from various centres in North America and Ireland. Data were analyzed to explore any relationships between feeding and biochemical or clinical features, effects of treatment, and to identify a potential mechanism. RESULTS Fifty-one children were identified at 17 institutions with EF-associated hypophosphatemia. Most children had complex illnesses and had been solely fed Neocate® formula products for variable periods of time prior to presentation. Feeding methods varied. Hypophosphatemia was detected during evaluation of fractures or rickets. Increased alkaline phosphatase activity and appropriate renal conservation of phosphate were documented in nearly all cases. Skeletal radiographs demonstrated fractures, undermineralization, or rickets in 94% of the cases. Although the skeletal disease had often been attributed to underlying disease, most all improved with addition of supplemental phosphate or change to a different formula product. CONCLUSION The observed biochemical profiles indicated a deficient dietary supply or severe malabsorption of phosphate, despite adequate formula composition. When transition to an alternate formula was possible, biochemical status improved shortly after introduction to the alternate formula, with eventual improvement of skeletal abnormalities. These observations strongly implicate that bioavailability of formula phosphorus may be impaired in certain clinical settings. The widespread nature of the findings lead us to strongly recommend careful monitoring of mineral metabolism in children fed EF. Transition to alternative formula use or implementation of phosphate supplementation should be performed cautiously with as severe hypocalcemia may develop.

Fear of hypoglycemia in parents of children with type 1 diabetes

The aim of this study is to determine if parental hypoglycaemia fear is associated with worse glycaemic control and increased resource utilisation and to identify risk factors for increased hypoglycaemia fear.

Lack of sensitivity of the 1‐μg low‐dose ACTH stimulation test in a paediatric population with suboptimal cortisol responses to insulin‐induced hypoglycaemia

The insulin‐tolerance test (ITT) is the gold standard for evaluation of the hypothalamic‐pituitary‐adrenal (HPA) axis. The low‐dose ACTH stimulation test is increasingly used for evaluation of secondary adrenal insufficiency as several studies performed in adults have demonstrated high sensitivity and specificity when compared to the ITT. Whether the ACTH stimulation test demonstrates similar sensitivity in a paediatric and adolescent population compared with the gold standard is unclear.

Requirement for age-specific peak cortisol responses to insulin-induced hypoglycaemia in children

OBJECTIVE Based on adult data, a peak cortisol response ≥500 nmol/l to insulin-induced hypoglycaemia constitutes a normal. Age-specific reference ranges for basal morning cortisol have been developed for clinical use in the paediatric population. Such reference ranges are not clearly established for peak cortisol responses to insulin-induced hypoglycaemia despite limited data suggesting an effect of age on peak cortisol. The aims of this study were to assess factors affecting the cortisol response to insulin-induced hypoglycaemia in children and to determine whether the peak cortisol response was related to age. DESIGN The present study was a retrospective cohort study. METHODS Retrospective analysis of children and adolescents aged ≤18 years undergoing the insulin tolerance test with adequate hypoglycaemia was undertaken. Patients with hypopituitarism or severe hypothalamic-pituitary-adrenal axis impairment (peak cortisol value <400 nmol/l) or using systemic glucocorticoids were excluded. RESULTS Two hundred and twenty-three tests were analysed. Peak cortisol responses ≥500 nmol/l occurred in 183 (82%) tests. Age was negatively associated with peak cortisol responses (r=-0.15, P=0.03). A peak cortisol response <500 nmol/l was significantly less common in patients aged <12 years (9/97 (9%) vs 31/126 (25%); P=0.004). In children aged <12 years, the median (5th-95th centiles) peak cortisol values were 610 (480-806) nmol/l compared with 574 (442-789) nmol/l in children aged ≥12 years (P<0.004). Similarly, median cortisol increment was significantly higher in younger patients (301 nmol/l compared with 226 nmol/l (P=0.0004)). CONCLUSIONS Use of a single peak cortisol threshold in children of all ages is not appropriate and will result in overdiagnosis of adrenal insufficiency in adolescents.

NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient

Childhood obesity is a major global concern, with over 50 million children now classified as obese. Obesity has been linked to the development of numerous chronic inflammatory diseases, including type 2 diabetes and multiple cancers. NK cells are a subset of innate effector cells, which play an important role in the regulation of adipose tissue and antitumor immunity. NK cells can spontaneously kill transformed cells and coordinate subsequent immune responses through their production of cytokines. We investigated the effect of obesity on NK cells in a cohort of obese children, compared to children with a healthy weight. We demonstrated a reduction in peripheral NK cell frequencies in childhood obesity and inverse correlations with body mass index and insulin resistance. Compared with NK cells from children with normal weight, we show increased NK cell activation and metabolism in obese children (PD-1, mTOR activation, ECAR, and mitochondrial ROS), along with a reduced capacity to respond to stimulus, ultimately leading to loss of function (proliferation and tumor lysis). Collectively we show that NK cells from obese children are activated, metabolically stressed, and losing the ability to perform their basic duties. Paired with the reduction in NK cell frequencies in childhood obesity, this suggests that the negative effect on antitumor immunity is present early in the life course of obesity and certainly many years before the development of overt malignancies.

Catalogue of inherited disorders found among the Irish Traveller population

Background Irish Travellers are an endogamous, nomadic, ethnic minority population mostly resident on the island of Ireland with smaller populations in Europe and the USA. High levels of consanguinity result in many rare autosomal recessive disorders. Due to founder effects and endogamy, most recessive disorders are caused by specific homozygous mutations unique to this population. Key clinicians and scientists with experience in managing rare disorders seen in this population have developed a de facto advisory service on differential diagnoses to consider when faced with specific clinical scenarios. Objective(s) To catalogue all known inherited disorders found in the Irish Traveller population. Methods We performed detailed literature and database searches to identify relevant publications and the disease mutations of known genetic disorders found in Irish Travellers. Results We identified 104 genetic disorders: 90 inherited in an autosomal recessive manner; 13 autosomal dominant and one a recurring chromosomal duplication. Conclusion We have collated our experience of inherited disorders found in the Irish Traveller population to make it publically available through this publication to facilitate a targeted genetic approach to diagnostics in this ethnic group.

Serial GH Measurement After Intravenous Catheter Placement Alone Can Detect Levels Above Stimulation Test Thresholds in Children

CONTEXT GH stimulation testing is limited by poor specificity and reproducibility in identifying GH deficiency. Intravenous line placement (IVP) in pediatrics may be a stimulus for GH secretion. OBJECTIVE The objective of the study was to determine whether the measurement of GH at baseline as well as 15 and 30 minutes after IVP detects additional patients with sufficient peak GH concentrations who are not identified by a subsequent insulin tolerance test (ITT). METHODS The ITT protocol was modified to include GH measurement at the time of IVP (t = 0) and 15 (t = 15) and 30 (t = 30) minutes later. Insulin was administered at t = 30, and an ITT was performed as per standard protocols. Children were grouped according to the indication for ITT: initial evaluation of GH deficiency (group 1); and GH deficiency at transition to adulthood (group 2). RESULTS Ninety-seven patients were included (76 in group 1, 21 in group 2). Of these, 27 (28%) had a peak GH concentration of 7 ng/mL or greater (19 in group 1, eight in group 2) either after IVP or ITT. Thirteen subjects (11 in group 1, two in group 2) had GH concentrations of 7 ng/mL or greater after IVP, without exceeding this on a subsequent ITT. Among the 11 group 1 patients, three of these GH peaks of 7 ng/mL or greater occurred at t = 0, 5 at t = 15, and 5 at t = 30, including one patient who had a peak GH of 7 ng/mL or greater at all three time points. CONCLUSION Some children will not have a sufficient GH response to pharmacological stimuli but will have a robust response to IVP. We recommend GH measurement after IVP in children undergoing GH stimulation testing, particularly when there is a delay between IVP and the administration of the pharmacological stimulus.